KIF18A inhibitor and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to a KIF18A inhibitor, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and use of the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof in preparing a drug for treating and / or preventing diseases mediated by KIF18A and related diseases. Background Art

[0002] Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes. Various microtubule-associated proteins (MAPs) of the kinesin-8 family of kinesins regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules. It is reported that the kinesin family is closely related to the invasion, metastasis and poor prognosis of various cancers. An increasing number of kinesin family members are believed to be associated with the occurrence and progression of tumors. KIF18A is a member of the kinesin-8 family and is a multifunctional protein that uses adenosine triphosphate (ATP) hydrolysis to generate force and move along microtubules. It is involved in a variety of cellular functions, including cell division, cell movement, microtubule dynamics and organelle transport. KIF18A affects cell differentiation and cancer development. Studies have shown that KIF18A is associated with tumor behavior and can be used as a potential biomarker for breast cancer, colorectal cancer and hepatocellular carcinoma.

[0003] Genetic instability is a common feature of tumor cells, with a large number of tumor cells showing frequent loss or gain of chromosomes. This chromosomal instability (CIN) is mainly 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 show increased spindle microtubule polymerization and reduced turnover of attachments between spindle microtubules and kinetochores, which are specialized protein structures assembled at the centromeric regions of mitotic chromosomes. Therefore, CIN cells may be particularly vulnerable to anti-mitotic therapies that target 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 stops. 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 delays, multipolar spindles, and increased cell death. Therefore, KIF18A may be an effective target for specific inhibition of CIN tumor cell growth 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. Summary of the invention

[0006] The object of the present invention is to provide a KIF18A inhibitor and its application. The specific technical scheme is as follows:

[0007] 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:

[0008]

[0009] in,

[0010] X 1 Select from N or CR 1a ;

[0011] X 2 Selected from CR 2a R 2b or NR 2c ;

[0012] X 3 Select from N or CR 3a ;

[0013] X 4 Select from N or CR 4a ;

[0014] X 5 Select from N or CR 5a ;

[0015] Y1 is selected from N or CR 6a ;

[0016] Y2 is selected from N or CR 7a ;

[0017] L is selected from -NR-C(O)-, -C(O)-NR'-, -NR-S(O)-, -S(O)-NR'-, -NR-S(O)2- or -S(O)2-NR'-;

[0018] R, R' at each occurrence 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;

[0019] R 1 Selected from the following groups:

[0020] Each Q1 is independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents Q2; the substituents Q2 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;

[0021] R 1a , R 3a , R 4a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0022] R 2a , R 2b , R 2c Each occurrence is independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano or the following groups which are optionally substituted with 1 to 3 substituents Q3: 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 1-6Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -phenyl, -(CH2) m -5-6 membered heteroaryl, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0023] The Q3 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;

[0024] Each m and n is independently selected from 0, 1, 2 or 3.

[0025] 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 , X 5 At least one of them is N.

[0026] 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 , X 5 At least two of them are N.

[0027] 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 , X 5 There are at least three N.

[0028] 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 , X 5 There are at least four N.

[0029] 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 .

[0030] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 is N.

[0031] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 CR 2a R 2b .

[0032] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 NR 2c .

[0033] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 CR 3a .

[0034] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 is N.

[0035] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 CR 4a .

[0036] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 is N.

[0037] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 5 CR 5a .

[0038] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 5 is N.

[0039] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Y1 is CR 6a .

[0040] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Y1 is N.

[0041] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Y2 is CR 7a .

[0042] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Y2 is N.

[0043] In certain embodiments, L is selected from -NR-C(O)-, -C(O)-NR'-, -NR-S(O)-, -S(O)-NR'-, -NR-S(O)2-, or -S(O)2-NR'-; R, R' are each independently selected from hydrogen or C 1-6 alkyl.

[0044] In certain embodiments, L is selected from -NR-C(O)-, -C(O)-NR'-, -NR-S(O)-, -S(O)-NR'-, -NR-S(O)2-, or -S(O)2-NR'-; and R, R' at each occurrence are independently selected from hydrogen or methyl.

[0045] In certain embodiments, L is selected from -NR-C(O)- or -C(O)-NR'-; R, R' are independently selected at each occurrence from hydrogen or C 1-6 alkyl.

[0046] In certain embodiments, L is selected from -NR-C(O)- or -C(O)-NR'-; R, R' at each occurrence are independently selected from hydrogen or methyl.

[0047] In certain embodiments, L is selected from -NH-C(O)- or -C(O)-NH-.

[0048] In certain embodiments, R 1 Selected from the following groups:

[0049] In certain embodiments, each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6Alkoxy, or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents Q2; the substituents Q2 are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0050] In certain embodiments, each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0051] In certain embodiments, R 1a , R 3a , R 4a , R 5a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0052] In certain embodiments, R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0053] In certain embodiments, R 2a , R 2c is independently selected at each occurrence from hydrogen, halogen, or C optionally substituted with 1-3 Q3 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0054] The Q3 are independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0055] In certain embodiments, R 2b Each occurrence is independently selected from hydrogen or C 1-6 alkyl.

[0056] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (II),

[0057]

[0058] Wherein, Y1 is selected from N or CR 6a ;

[0059] Y2 is selected from N or CR 7a ;

[0060] R 1 Selected from

[0061] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0062] R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclobutyl;

[0063] Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0064] R 4a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0065] R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0066] m and n are independently selected from 0, 1 or 2.

[0067] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (II),

[0068]

[0069] Wherein, Y1 is selected from N or CR 6a ;

[0070] Y2 is selected from N or CR 7a ;

[0071] R 1 Selected from

[0072] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0073] R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclobutyl;

[0074] Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0075] R 4a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0076] R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0077] m and n are independently selected from 0, 1 or 2.

[0078] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (II),

[0079]

[0080] Wherein, Y1 is selected from N, Y2 is selected from N or CR 7a ; or Y2 is selected from N, Y1 is selected from N or CR 6a ;

[0081] R 1 Selected from

[0082] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0083] R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclobutyl;

[0084] Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0085] R 4a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0086] R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0087] m and n are independently selected from 0, 1 or 2.

[0088] In certain embodiments, the compound represented by the aforementioned general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein:

[0089] Y1 is selected from N or CR 6a ;

[0090] Y2 is selected from N or CR 7a ;

[0091] R1 Selected from

[0092] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0093] R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclopropyl;

[0094] Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0095] R 4a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0096] R 5a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0097] R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0098] m and n are independently selected from 0, 1 or 2.

[0099] In certain embodiments, the compound represented by the aforementioned general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a Selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0100] In certain embodiments, the compound represented by the aforementioned general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a Selected from halogen, C 1-4Alkyl or halogenated C 1-4 alkyl.

[0101] In certain embodiments, the compound represented by the aforementioned general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a Selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0102] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 4a Selected from fluorine or methyl.

[0103] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a is selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 4a Selected from fluorine or methyl.

[0104] In certain embodiments, the compound represented by the aforementioned general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a is selected from hydrogen, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 4a is selected from hydrogen or methyl.

[0105] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a Selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0106] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a Selected from halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0107] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5ais selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 5a is selected from hydrogen, fluorine or methyl.

[0108] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a is selected from hydrogen, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 5a is selected from hydrogen or methyl.

[0109] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6a , R 7a are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0110] In certain embodiments, the compound represented by the aforementioned general formula (I) or general formula (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6a , R 7a R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, propyl, monofluoromethyl, difluoromethyl or trifluoromethyl. 6a , R 7a are independently selected from hydrogen, fluorine or methyl.

[0111] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (II), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0112] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (II), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0113] In certain embodiments, in the compounds of the aforementioned general formula (I), general formula (II), their pharmaceutically acceptable salts, esters or stereoisomers thereof, each Q3 is independently a halogen; preferably, each Q3 is independently a fluorine.

[0114] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (III),

[0115]

[0116] Wherein, Y1 is selected from N or CR 6a ;

[0117] Y2 is selected from N or CR 7a ;

[0118] R 1 Selected from

[0119] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0120] R 1a , R 4a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0121] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0122] The Q3 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;

[0123] Each m and n is independently selected from 0, 1 or 2.

[0124] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (III), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0125] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (III), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1a , R 4a , R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0126] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (III), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1a , R 4a , R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0127] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (III), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0128] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (III), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 Q3.

[0129] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (III), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c is selected from cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, which are optionally substituted with 1 to 3 Q3.

[0130] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (III), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0131] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (IV),

[0132]

[0133] Wherein, Y1 is selected from N or CR 6a ;

[0134] Y2 is selected from N or CR 7a ;

[0135] R 1 Selected from

[0136] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0137] R 4a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0138] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0139] The Q3 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;

[0140] Each m and n is independently selected from 0, 1 or 2.

[0141] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (IV), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0142] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0143] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4ais selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0144] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0145] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0146] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0147] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2cis selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 Q3.

[0148] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c is selected from cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, which are optionally substituted with 1 to 3 Q3.

[0149] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (IV), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0150] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (V),

[0151]

[0152] Wherein, Y1 is selected from N or CR 6a ;

[0153] Y2 is selected from N or CR 7a ;

[0154] R 1 Selected from

[0155] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0156] R 1a , R 5a , R 6a , R 7aEach occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0157] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0158] The Q3 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;

[0159] Each m and n is independently selected from 0, 1 or 2.

[0160] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (V'),

[0161]

[0162] Wherein, Y1 is selected from N or CR 6a ;

[0163] Y2 is selected from N or CR 7a ;

[0164] And at least one of Y1 and Y2 is N;

[0165] R 1 Selected from

[0166] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0167] R 5a , R 6a , R7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0168] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0169] The Q3 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;

[0170] Each m and n is independently selected from 0, 1 or 2.

[0171] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (V), general formula (V'), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0172] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (V), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 1a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0173] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (V), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 1ais independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0174] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0175] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0176] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0177] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m-3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0178] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 2c is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 Q3.

[0179] In certain embodiments, the compound of the aforementioned general formula (I), general formula (V), general formula (V'), its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 2c is selected from cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, which are optionally substituted with 1 to 3 Q3.

[0180] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (V), general formula (V'), their pharmaceutically acceptable salts, esters or stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0181] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (VI),

[0182]

[0183] Among them, X 4 Selected from CR 4a or N;

[0184] Y1 is selected from N or CR 6a ;

[0185] Y2 is selected from N or CR 7a ;

[0186] R 1 Selected from

[0187] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0188] R 4a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0189] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0190] The Q3 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;

[0191] Each m and n is independently selected from 0, 1 or 2.

[0192] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VI), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0193] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VI), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a , R 5a , R 6a , R 7ais independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 In certain embodiments, R 4a , R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen or C 1-6 alkyl.

[0194] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VI), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 4a , R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. In certain embodiments, R 4a , R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, methyl or trifluoromethyl.

[0195] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VI), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0196] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VI), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2cis selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 the following groups optionally substituted by 1-3 Q3: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl.

[0197] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VI), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c is selected from cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, which are optionally substituted with 1 to 3 Q3.

[0198] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VI), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0199] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (VII),

[0200]

[0201] in,

[0202] Y1 is selected from N or CR 6a ;

[0203] Y2 is selected from N or CR 7a ;

[0204] R 1 Selected from

[0205] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0206] R 5a , R6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0207] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0208] The Q3 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;

[0209] Each m and n is independently selected from 0, 1 or 2.

[0210] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0211] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 In certain embodiments, R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen or C 1-6 alkyl.

[0212] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. In certain embodiments, R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, methyl or trifluoromethyl.

[0213] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halo C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0214] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from C 1-6 Alkyl, haloC 1-6 Alkyl, or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0215] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2cis selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 the following groups optionally substituted by 1-3 Q3: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl.

[0216] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from C 1-6 Alkyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl optionally substituted by 1-3 Q3.

[0217] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0218] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure represented by the general formula (VIII),

[0219]

[0220] in,

[0221] Y1 is selected from N or CR 6a ;

[0222] Y2 is selected from N or CR 7a ;

[0223] R 1 Selected from

[0224] Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0225] R5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0226] R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group;

[0227] The Q3 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;

[0228] Each m and n is independently selected from 0, 1 or 2.

[0229] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0230] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VIII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 In certain embodiments, R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen or C 1-6 alkyl.

[0231] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VIII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. In certain embodiments, R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, methyl or trifluoromethyl.

[0232] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VIII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halo C 1-3 Alkyl-OC 1-2 Alkylene or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0233] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VIII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c Selected from C 1-6 Alkyl, haloC 1-6 Alkyl, or optionally substituted by 1-3 Q3 as follows: -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group.

[0234] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VIII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2cis selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 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 the following groups optionally substituted by 1-3 Q3: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl.

[0235] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (VII), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2c is selected from cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, which are optionally substituted with 1 to 3 Q3.

[0236] In certain embodiments, the compounds of the aforementioned general formula (I) or general formula (VII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0237] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein each Q3 is independently selected from halogen or C 1-4 Alkyl; preferably, each Q3 is independently selected from fluorine or methyl.

[0238] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein Y1 is selected from CR 6a or N; Y2 is CR 7a .

[0239] In certain embodiments, the compounds of the aforementioned formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V'), formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein Y1 is N; Y2 is selected from CR 7a .

[0240] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein Y1 is selected from CR 6a Or N; Y2 is N.

[0241] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein Y1 is selected from CH or N; and Y2 is CH.

[0242] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein Y1 is N; Y2 is CH.

[0243] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein Y1 is CH; Y2 is N or CH.

[0244] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein n is 0.

[0245] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, their esters or their stereoisomers, wherein m is 0.

[0246] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein R 1a For hydrogen.

[0247] In certain embodiments, the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V'), general formula (VI), (VII), (VIII), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein R 5a For hydrogen.

[0248] In some embodiments of the present invention, the structure of the provided compound, its pharmaceutically acceptable salt or its stereoisomer is as follows:

[0249]

[0250]

[0251]

[0252] The present invention also provides a pharmaceutical composition, which contains the compound described in the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer, and one or more second therapeutically active agents. Optionally, the pharmaceutical composition also contains one or more pharmaceutically acceptable carriers and / or diluents.

[0253] The second therapeutic agent described in the present invention includes but is not limited to growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotic agents, angiogenesis inhibitors, biological response modifiers, antihormones, and anticancer drugs.

[0254] The present invention also provides a pharmaceutical preparation, which contains the compound described in the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is any dosage form that is clinically or pharmaceutically acceptable.

[0255] In some embodiments of the present invention, the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or pulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, adhesives, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives can be omitted or appropriate additives can be added according to the properties of the drugs. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition can be made into inhalants or sprays, etc.

[0256] The pharmaceutical carrier and / or diluent available in the pharmaceutical composition of the present invention or the pharmaceutical preparation can be any conventional carrier and / or diluent in the pharmaceutical preparation field, and the selection of specific carrier and / or diluent will depend on the mode of administration or disease type and state for treating a specific patient. The preparation method of the suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of the pharmaceutical field technician. For example, the pharmaceutical carrier and / or diluent can include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. in the pharmaceutical composition. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0257] The present invention also provides the use of the compound described in the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a drug 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.

[0258] The present invention also provides the use of the compound described in the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment and / or prevention of KIF18A-mediated diseases and related diseases; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.

[0259] The present invention also provides a method for treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, 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.

[0260] 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.

[0261] In the specification and claims of the present 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 representing the same compound, the chemical structural formula shall prevail.

[0262] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

[0263] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0264] The term "halogenated" as used herein means that any hydrogen in the substituent may be replaced by one or more halogens which may be the same or different. "Halogen" is as defined above.

[0265] 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", "C3-4 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.

[0266] The "C 1-6 "Alkylene" refers to the above-mentioned C 1-6 The radical 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 C 1-6 Specific examples of the alkylene group contain 1 to 4 carbon atoms.

[0267] 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 1-6 Alkylaminosulfonyl, 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 The group formed by alkyl-OC(O)-, wherein "C 1-6 "Alkyl" is as defined above.

[0268] 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 The group formed by alkyl-OC(O)-, wherein "C 1-4 "Alkyl" is as defined above.

[0269] 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., which are substituted by C 1-6 Alkyl, C 1-6Alkylene, C 1-6 A group formed by the hydrogen atoms in an alkoxy group.

[0270] 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, etc., which are substituted by C 1-4 Alkyl, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0271] The "3-6 membered cycloalkyl" of the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-6 carbon atoms and not having aromaticity, including "3-6 membered saturated cycloalkyl" and "3-6 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "5-6 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl" and the like. Specific examples of the "3-6 membered saturated cycloalkyl" include, but are not limited to, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl); specific examples of the "3-6 membered partially saturated cycloalkyl" include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, cyclopentadienyl, cyclohexene, cyclohexa-1,3-diene, cyclohexa-1,4-diene and the like.

[0272] The "3-6 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic group having 3-6 ring atoms and not having aromaticity, which contains at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and the number of ring atoms is 3-6, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure may be oxo-substituted. Preferably, the "3-6 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-6 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 "3-6 membered heterocyclic group" of the present invention contains 1 nitrogen atom. Specific examples of the "3-6 membered heterocyclic group" include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diaziridine, azetidinyl, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, Piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridonyl, dihydropiperidonyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 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, and the like.

[0273] The "5-6 membered heteroaryl" of the present invention refers to a monocyclic cyclic group having aromaticity and containing 5-6 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. Specific examples of the “5-6 membered heteroaryl” include but are not limited to furanyl, 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 and 1,2,4,5-tetrazinyl.

[0274] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0275] The "pharmaceutically acceptable salt" described in the present invention refers 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.

[0276] The "ester" of the present invention refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes an ester that is easily decomposed in the human body to leave the parent compound (the compound of general 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 part of the carboxylic acid compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight 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 (e.g. 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 alcohol compounds, wherein the non-hydroxyl portion of the alcohol compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight 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 (e.g. 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 1-4Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0277] The "stereoisomer" of the present invention refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, unless otherwise specified, cis isomers and trans isomers are included. The compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included in the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds are included in the scope of the present invention.

[0278] The "therapeutically effective amount" of the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least alleviate the symptoms of the patient's condition when administered to the patient. The actual amount comprising the "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 and health condition, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.

[0279] Advantageous Effects of the Invention

[0280] (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;

[0281] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0282] (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;

[0283] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0284] (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.

[0285] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be understood as the compounds provided in the embodiments of the present invention only having the following beneficial effects.

[0286] Experimental Example 1 In vitro cytological activity of the compounds of the present invention

[0287] Test samples: some compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0288] The cell lines used in the following experiments are as follows:

[0289] OVCAR3: TP53 mutant human ovarian cancer cells

[0290] MDA-MB-157: TP53 mutant human breast cancer cells

[0291] Experimental method (CelltiterGlo assay)

[0292] 1. Cell Preparation

[0293] 1.1 Cell culture:

[0294] 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.

[0295] 1.2 Preparation of cell suspension:

[0296] Harvest cells in the logarithmic growth phase and count them using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to an appropriate concentration and add 90 μL of the cell suspension to each 96-well plate.

[0297] Table 1 Number of cells seeded

[0298]

[0299] 2. Preparation of test compounds

[0300] 2.1 Prepare DMSO stock solution of the test compound. The concentration of the stock solution of the test compound is 10 mM.

[0301] 2.2 Preparation of test compound working stock solution

[0302] The test compound stock solution was 10 mM, and was diluted 3 times in series, with a total of 9 concentrations. Then, 2 μL of the DMSO-diluted compound was added to 198 μL of culture medium to form the test compound working stock solution (the compound concentration was 10 times the final concentration, and the highest concentration was 100 μM).

[0303] 2.3 Compound treatment

[0304] 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.

[0305] The final concentrations of the tested 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.

[0306] 2.4 Control well setting

[0307] Solvent control: 0.1% DMSO.

[0308] Blank control: culture medium

[0309] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 4 days.

[0310] 3. Detection

[0311] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes, add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake on an oscillator for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value with a multifunctional microplate reader.

[0312] 4. Data Processing

[0313] 1) Inhibition rate (%) = 1-(test well reading-blank control well reading) / (DMSO solvent control well reading-blank control well reading) × 100%;

[0314] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0315] Experimental results and conclusions

[0316] Table 2 In vitro cytological activities (IC 50 ,nM)

[0317]

[0318]

[0319] A: IC 50 <100nM; B: 100nM≤IC 50 <200nM; C: 200nM≤IC 50 <1 μM;

[0320] 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 for treating cancerous diseases with TP53 mutations. DETAILED DESCRIPTION

[0321] The technical solution of the present invention will be described below in conjunction with specific embodiments, and the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0322] DMF: N,N-dimethylformamide EA: ethyl acetate PE: petroleum ether

[0323] DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DEAD: diethyl azodicarboxylate

[0324] NaH: Sodium hydride TFA: Trifluoroacetic acid Boc-NH2: Tert-butyl carbamate

[0325] DMSO: dimethyl sulfoxide CuI: cuprous iodide m-CPBA: m-chloroperbenzoic acid Pd2dba3: tris(dibenzylideneacetone)dipalladium MTBE: methyl tert-butyl ether DMEDA: N,N'-dimethylethylenediamine RuPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0326] Breatphos Pd G3: methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene Selective fluorine reagent: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt

[0327] Example 1: Preparation of N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 2)

[0328]

[0329] 1. Preparation of 6-chloro-3-fluoro-1H-pyrazolo[3,4-b]pyridine (Int-2)

[0330] 6-Chloro-1H-pyrazolo[3,4-b]pyridine (compound Int-1, 250 mg, 1.6 mmol) was dissolved in acetonitrile (25 mL), and a selective fluorine reagent (1.7 g, 4.8 mmol) was added. The system was heated to 100° C. for 3 h, and then concentrated. 210 mg of the target product was obtained by column chromatography (EA:PE=1:1) with a yield of 75.2%.

[0331] 2. Preparation of 6-chloro-1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridine (Int-3)

[0332] Dissolve compound Int-2 (200 mg, 1.2 mmol), 3,3-difluorocyclobutanol (155 mg, 1.4 mmol) and triphenylphosphine (450 mg, 1.7 mmol) in THF (100 mL), add DEAD (300 mg, 1.7 mmol). React at 25°C for 16 hours. Quench the system with water, extract with EA, dry, concentrate, and purify with silica gel column chromatography (EA:PE=1:6) to obtain 210 mg of the target compound, yield: 68.9%.

[0333] 3. Preparation of tert-butyl (1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (Int-4)

[0334] Compound Int-3 (200 mg, 0.76 mmol) and Boc-NH2 (140 mg, 1.2 mmol) were dissolved in 1,4-dioxane (100 mL), and RuPhosPdG3 (20 mg) and cesium carbonate (500 mg, 1.5 mmol) were added, and the mixture was ventilated with nitrogen for 3 times, and reacted at 100°C for 3 hours under nitrogen protection. The system was quenched with water, and the organic phase was extracted with EA, dried, concentrated, and purified by silica gel column chromatography (EA:PE=1:4) to obtain 220 mg of the target compound with a yield of 84.1%.

[0335] 4. Preparation of 1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-5)

[0336] Compound Int-4 (200 mg, 0.58 mmol) was dissolved in DCM (10 mL), and 2 mL of TFA was added, and the mixture was reacted at 25°C for 1 h. Water was added to quench the mixture, and the pH was adjusted to 7 with sodium bicarbonate solution. EA was added for extraction, and the crude product was concentrated to obtain 120 mg of the product with a yield of 84.8%.

[0337] 5. Preparation of N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-7)

[0338] Compound Int-5 (100 mg, 0.41 mmol) was dissolved in DMF (50 mL), cooled to 0°C, NaH (60%) (80 mg, 2.0 mmol) was added, stirred at 0°C for 20 minutes, 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (compound Int-6, 330 mg, 0.88 mmol) was added, and the reaction was continued at 25°C for 2 hours. After the reaction was completed, the mixture was extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (EA:PE=1:2) to obtain 210 mg of the target compound, with a yield of 87.5%.

[0339] 6. Preparation of N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 2)

[0340] Compound Int-7 (180 mg, 0.31 mmol) and 2-hydroxyethane-1-sulfonamide (compound Int-8, 120 mg, 0.96 mmol) were dissolved in DMF (50 mL), and CuI (80 mg, 0.42 mmol), DMEDA (101 mg, 1.1 mmol) and potassium phosphate (180 mg, 0.85 mmol) were added, ventilated with nitrogen for 3 times, and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench, extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 25: 1) to obtain 150 mg of the target compound, with a yield of 83.7%.

[0341] Molecular formula: C 26 H 29 F3N6O4S molecular weight: 578.6 LC-MS (M / e): 579.1 (M+H+ )

[0342] Example 1-1: Preparation of N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide sodium salt (Compound 2-1)

[0343]

[0344] Compound 2 (100 mg, 0.17 mmol) was dissolved in methanol (20 mL), sodium hydroxide (15 mg, 0.38 mmol) was added, and the mixture was stirred at 25° C. for 15 minutes and concentrated to obtain 110 mg of the product.

[0345] Molecular formula: C 26 H 27 F3N6Na2O4S molecular weight: 622.6 LC-MS (M / e): 579.1 (M+H + )

[0346] 1 H-NMR (400MHz, CDCl3) δ: 7.46-7.43 (m, 2H), 7.11-7.09 (m, 1H), 6.37-6.33 (m, 1H), 6.31 (s, 1H), 5.41-5.31 (m, 1H), 3.66-3.62 (m, 2H), 3.19-3.02 (m, 5H), 2.95-2.80 (m, 6H), 1.30-1.26 (m, 4H), 0.26-0.19 (m, 4H). Example 2: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 3)

[0347]

[0348] 1. Preparation of 6-chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazine (Int-12)

[0349] Dissolve 6-chloro-1H-pyrazolo[3,4-b]pyrazine (Compound Int-10, 8.0 g, 51.7 mmol), 3,3-difluorocyclobutanol (6.1 g, 56.4 mmol) and triphenylphosphine (17.6 g, 67.1 mmol) in THF (100 mL), add DEAD (13.5 g, 77.5 mmol). React at 25°C for 16 hours. Quench the system with water, extract with EA, dry, concentrate, and purify with silica gel column chromatography (EA:PE=1:6) to obtain 6.2 g of the target compound, with a yield of 49.0%.

[0350] 2. Preparation of tert-butyl (1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)carbamate (Int-13)

[0351] Compound Int-12 (6.2 g, 25.3 mmol) and Boc-NH2 (5.9 g, 50.4 mmol) were dissolved in 1,4-dioxane (100 mL), and RuPhos Pd G3 (2.1 g, 2.5 mmol) and cesium carbonate (24.7 g, 75.8 mmol) were added, and the mixture was ventilated with nitrogen for 3 times, and reacted at 100°C for 3 hours under nitrogen protection. The system was quenched with water, and the organic phase was extracted with EA, dried, concentrated, and purified by silica gel column chromatography (EA:PE=1:4) to obtain 6.6 g of the target compound with a yield of 80.0%.

[0352] 3. Preparation of 1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazine-6-amine (Int-14)

[0353] Compound Int-13 (6.6 g, 2.5 mmol) was dissolved in DCM (100 mL), TFA (25 mL) was added, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was diluted with DCM, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated to obtain 4.2 g of the target compound with a yield of 91.9%.

[0354] 4. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-15)

[0355] Compound Int-14 (1.0 g, 4.4 mmol) was dissolved in DMF (50 mL), cooled to 0°C, NaH (60%) (880 mg, 22.0 mmol) was added, stirred at 0°C for 20 minutes, compound Int-6 (3.3 g, 8.8 mmol) was added, and the reaction was continued at 25°C for 2 hours. After the reaction was completed, the mixture was extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (EA: PE = 1: 2) to obtain 650 mg of the target compound, with a yield of 25.9%.

[0356] 5. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 3)

[0357] Compound Int-15 (650 mg, 1.2 mmol) and compound Int-8 (432 mg, 3.5 mmol) were dissolved in DMF (50 mL), and CuI (220 mg, 1.2 mmol), DMEDA (101 mg, 1.1 mmol) and potassium phosphate (1.2 g, 5.7 mmol) were added, ventilated with nitrogen for 3 times, and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench, extracted with water and EA, and the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 25:1) to obtain 400 mg of the target compound with a yield of 61.8%.

[0358] Molecular formula: C 25 H 29 F2N7O4S molecular weight: 561.6 LC-MS (M / e): 562.2 (M+H + )

[0359] Example 2-1: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide disodium salt (Compound 3-1)

[0360]

[0361] Compound 3 (400 mg, 0.71 mmol) was dissolved in methanol (20 mL), sodium hydroxide (63 mg, 1.6 mmol) was added, and the mixture was stirred at 25° C. for 15 minutes and concentrated to obtain 460 mg of the product.

[0362] Molecular formula: C 25 H 27F2N7Na2O4S molecular weight: 605.6 LC-MS (M / e): 562.2 (M+H + )

[0363] 1 H-NMR (400MHz, DMSO-d6)δ:8.51(s,1H),7.88(s,1H),7.15(d,J=8.0Hz,1H),6.41-6.31(m,2H),5.22- 5.15(m,1H),3.69-3.62(m,1H),3.30-3.02(m,4H),2.95-2.82(m,6H),1.37-1.28(m,4H),0.22(s,4H).

[0364] Example 3: Preparation of N-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 4)

[0365]

[0366]

[0367] 1. Preparation of tert-butyl (1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (Int-17)

[0368] Boc-NH2 (4.5 g, 38.2 mmol), RuPhosPdG3 (1.6 g, 1.9 mmol) and cesium carbonate (18.7 g, 57.3 mmol) were added to 6-chloro-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine (compound Int-16, 3.7 g, 19.1 mmol) in 1,4-dioxane (50 mL), and the mixture was reacted at 100°C for 3 hours under nitrogen protection. The system was quenched with water, the organic phase was extracted with EA, dried, concentrated, and the residue was purified by silica gel column (EA:PE=1:3) to obtain 2.8 g of the target compound, with a yield of 53.4%.

[0369] 2. Preparation of 1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-18)

[0370] At 25°C, TFA (1 mL) was added to a solution of compound Int-17 (2.8 g, 10.2 mmol) in DCM (20 mL) and the mixture was reacted for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was diluted with DCM. The pH was adjusted to alkaline with saturated sodium bicarbonate, and the organic phase was extracted with DCM, dried, and spin-dried to obtain 1.6 g of the target compound with a yield of 89.9%.

[0371] 3. Preparation of N-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-19)

[0372] Potassium phosphate (2.0 g, 9.2 mmol), DIPEA (7.1 g, 55.2 mmol) and compound Int-18 (1.6 g, 9.2 mmol) were added to compound Int-6 (3.5 g, 9.2 mmol) in DCM (50 mL) at 0°C, and the reaction was continued at 25°C for 2 hours. After the reaction was completed, the product was concentrated and the residue was purified by silica gel column (EA:PE=1:3) to obtain 3.9 g of the target compound with a yield of 82.6%.

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

[0374] Compound Int-19 (3.9 g, 7.6 mmol) and compound Int-8 (2.96 g, 22.8 mmol) were dissolved in DMF (50 mL), and CuI (1.4 g, 7.6 mmol), DMEDA (670 mg, 7.6 mmol) and potassium phosphate (4.8 g, 22.8 mmol) were added, and the mixture was ventilated with nitrogen for 3 times, and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench, and the mixture was extracted with water and EA. The organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 25:1) to obtain 1.2 g of the target compound with a yield of 30.9%.

[0375] Molecular formula: C 25 H 30 N6O4S molecular weight: 510.6 LC-MS (M / e): 511.6 (M+H + )

[0376] Example 3-1: Preparation of N-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide disodium salt (Compound 4-1)

[0377]

[0378] Compound 4 (100 mg, 0.2 mmol) was dissolved in methanol (2 mL), sodium hydroxide (8 mg, 0.2 mmol) was added, and the mixture was stirred at 25° C. for 15 minutes and concentrated to obtain 104 mg of the product.

[0379] Molecular formula: C 25 H 28 N6Na2O4S molecular weight: 554.6 LC-MS (M / e): 511.0 (M+H + )

[0380] 1 H-NMR (400 MHz, DMSO-d6) δ: 14.0 (d, 1H), 8.25 (m, 1H), 8.15 (m, 1H), 7.95 (s, 1H), 7.8 (m, 1H), 6.85 (s, 1H), 6.7 (m, 1H), 5.0 (m, 1H), 3.75 (m, 4H), 3.33 (m, 2H), 2.95 (m, 6H), 1.15 (m, 4H), 0.45 (m, 4H). Example 4: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 5)

[0381]

[0382] 1. Preparation of 5-bromo-N-(3,3-difluorocyclobutyl)-2-nitroaniline (Int-22)

[0383] 4-Bromo-2-fluoro-1-nitrobenzene (Compound Int-20, 2.0 g, 9.1 mmol) and 3,3-difluorocyclobutane-1-amine hydrochloride (Compound Int-21, 2.0 g, 13.9 mmol) were dissolved in 1,4-dioxane (50 mL), and DIPEA (3.5 g, 27.1 mmol) was added. The mixture was reacted at 75° C. for 16 hours, concentrated, and purified by silica gel column chromatography (EA: PE = 1:6) to obtain 2.5 g of the target compound, with a yield of 89.5%.

[0384] 2.5-Bromo-N 1 Preparation of -(3,3-difluorocyclobutyl)benzene-1,2-diamine (Int-23)

[0385] Dissolve compound Int-22 (2.4 g, 7.8 mmol) in THF (30 mL) / methanol (30 mL) / water (6 mL), add zinc powder (4.1 g, 62.7 mmol) and ammonium chloride (4.2 g, 78.5 mmol). React at 60°C for 2 hours. Filter the system, concentrate, extract with EA, dry, and concentrate to obtain 2.0 g of crude product, which is used directly in the next step.

[0386] 3. Preparation of 6-bromo-1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazole (Int-24)

[0387] Compound Int-23 (crude product) was dissolved in acetic acid (30 mL), sodium nitrite (996 mg, 14.4 mmol) was added, and the mixture was reacted at 25°C for 1 hour, water was added, and the mixture was reacted at 25°C for 0.5 hour until the reaction was complete. The mixture was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with EA twice to obtain 2.1 g of the crude product, which was used directly in the next step.

[0388] 4. Preparation of tert-butyl (1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazol-6-yl)carbamate (Int-25)

[0389] Compound Int-24 (crude product) and tert-butyl carbamate (1.7 g, 14.5 mmol) were dissolved in 1,4-dioxane (60 mL), and RuPhosPdG3 (610 mg, 0.73 mmol) and cesium carbonate (7.1 g, 21.8 mmol) were added, and the mixture was ventilated with nitrogen for 3 times, and reacted at 100°C for 3 hours under nitrogen protection. The system was quenched with water, and the organic phase was extracted with EA, dried, concentrated, and purified by silica gel column chromatography (EA:PE=1:4) to obtain 2.0 g of the target compound, with a three-step yield of 78.9%.

[0390] 5. Preparation of 1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazole-6-amine (Int-26)

[0391] Compound Int-25 (2.0 g, 6.2 mmol) was dissolved in DCM (30 mL), trifluoroacetic acid (10 mL) was added, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was diluted with DCM, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The organic phase was extracted with DCM, dried, and concentrated to obtain 1.2 g of the target compound with a yield of 86.8%.

[0392] 6. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-27)

[0393] Compound Int-26 (1.2 g, 5.4 mmol) and DIPEA (2.1 g, 16.3 mmol) were dissolved in 1,4-dioxane (50 mL), and compound Int-6 (2.5 g, 6.7 mmol) was added, and the reaction was continued at 25°C for 2 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (EA:PE=1:2) to obtain 2.5 g of the target compound, with a yield of 82.9%.

[0394] 7. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide sodium salt (Compound 5)

[0395] Compound Int-27 (500 mg, 0.89 mmol) and compound Int-8 (333 mg, 2.7 mmol) were dissolved in DMF (20 mL), and cuprous iodide (170 mg, 0.892 mmol), DMEDA (78 mg, 0.88 mmol) and potassium phosphate (945 mg, 4.5 mmol) were added, ventilated with nitrogen three times, and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench, extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 25: 1) to obtain 340 mg of the target compound, with a yield of 68.3%.

[0396] Molecular formula: C 26 H 30 F2N6O4S molecular weight: 560.6 LC-MS (M / e): 561.2 (M+H + )

[0397] Example 4-1: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide sodium salt (Compound 5-1)

[0398]

[0399] Compound 5 (60 mg, 0.11 mmol) was dissolved in methanol (5 mL), sodium hydroxide (10 mg, 0.25 mmol) was added, and the mixture was stirred at 25° C. for 15 minutes and concentrated to obtain 70 mg of the product.

[0400] Molecular formula: C 26 H 29 F2N6NaO4S molecular weight: 582.2 LC-MS (M / e): 561.2 (M+H + )

[0401] 1 H-NMR (400MHz, DMSO-d6) δ: 12.86 (s, 1H), 8.60 (s, 1H), 8.07 (d, J = 8.0Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.36 (d, J = 8.8Hz, 1H), 6.82 (s, 1H), 6.67 (d ,J=8.8Hz,1H),5.44-5.42(m,1H),5.04-4.95(m,1H),3.78-3.62(m,2H) ,3.55-3.40(m,4H),3.05-2.88(m,6H),1.80-1.65(m,4H),0.38(s,4H).

[0402] Example 5: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 6)

[0403]

[0404] Compound Int-15 (250 mg, 0.44 mmol) was dissolved in DMSO (5 mL), 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, and the mixture was reacted at 140°C in a microwave oven under nitrogen protection for 1 hour. The reaction was completed. The mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with EA, and the concentrated residue was purified by silica gel column (EA:PE=47%), slurried with EA, filtered, and dried to obtain 80 mg of the target compound, with a yield of 33.5%.

[0405] Molecular formula: C 26 H 28 F2N6O3S molecular weight: 542.6 LC-MS (M / e): 543.2 (M+H + )

[0406] Example 5-1: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide sodium salt (Compound 6-1)

[0407]

[0408] Compound 6 (70 mg, 0.13 mmol) was dissolved in methanol (2 mL), sodium hydroxide (6 mg, 0.16 mmol) was added, and the mixture was stirred at 25° C. for 15 minutes and concentrated to obtain 70 mg of the product.

[0409] Molecular formula: C 26 H 27 F2N6NaO3S molecular weight: 564.6 LC-MS (M / e): 543.2 (M+H + )

[0410] 1 H-NMR(400MHz,DMSO-d6)δ:8.64(s,1H),7.98(s,1H),7.48-7.46(m,1H),7.32-7.30(m,1H),7.23(s,1H),5.07 -5.05(m,1H),3.26-3.03(m,6H),1.39-1.38(m,4H),1.07-1.03(m,2H),1.02-1.01(m,2H),0.27-0.24(m,4H).

[0411] Example 6: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 7)

[0412]

[0413] 1. Preparation of methyl 2-((4-((1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)thio)acetate (Int-28)

[0414] Compound Int-15 (500 mg, 0.89 mmol) was dissolved in 1,4-dioxane (30 mL), and methyl thioglycolate (200 mg, 0.1.9 mmol), Pd2dba3 (100 mg) and XantPhos (100 mg) were added. The mixture was reacted at 100 °C for 1 hour under nitrogen protection, and the reaction was completed. Saturated sodium bicarbonate aqueous solution was added to quench the mixture, and EA was extracted. The concentrated residue was purified by silica gel column (EA:PE=47%), EA was used for pulping, filtration was performed, and the crude target compound (500 mg) was obtained by spin drying.

[0415] 2. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-29)

[0416] Dissolve compound Int-28 (300 mg, 0.53 mmol) in methanol (10 mL), add sodium borohydride (65 mg, 1.7 mmol), and react at 25°C for 1 hour. Quench the system with water, extract with EA, dry, concentrate, and purify with silica gel column chromatography (MeOH:DCM=1:15) to obtain 210 mg crude product of the target compound.

[0417] 3. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 7)

[0418] Compound Int-29 (30 mg) was dissolved in DCM (10 mL), and m-CPBA (30 mg) was added and reacted at 25°C for 3 hours. The system was quenched with water, and the organic phase was extracted with EA, dried, concentrated, and purified by silica gel column chromatography (MeOH: DCM = 1: 10) to obtain 15 mg of the target compound.

[0419] Molecular formula: C 25 H 28 F2N6O4S molecular weight: 546.6 LC-MS (M / e): 547.1 (M+H + )

[0420] 1 H-NMR(400MHz, CDCl3)δ:13.76(m,1H),9.59(m,1H),8.51(s,1H),8.27-8.26(m,1H),7.95-7.83(m,1H),7.81(m, 1H),5.31-5.20(m,1H),4.94(s,1H),3.75-3.74(m,2H),3.59-3.14(m,8H),1.96-1.72(m,4H),0.56-0.40(m,4H).

[0421] Example 7: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 8)

[0422]

[0423] Compound Int-7 (600 mg, 1.0 mmol) was dissolved in DMSO (5 mL), sodium cyclopropanesulfonate (256 mg, 2.0 mmol), potassium carbonate (55 mg, 0.4 mmol), CuI (386 mg, 0.2 mmol) and L-proline (923 mg, 0.2 mmol) were added, and the mixture was reacted at 130°C for 2 hours under nitrogen protection. The reaction was completed. Saturated sodium bicarbonate aqueous solution was added to quench the mixture, and EA was extracted. The residue was concentrated and purified by silica gel column (EA:PE=47%), EA was used for pulping, filtered, and the target compound (130 mg, yield: 22.5%) was obtained by spin drying.

[0424] Example 7-1: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide sodium salt (Compound 8-1)

[0425]

[0426] Compound 8 (120 mg, 0.2 mmol) was dissolved in methanol (10 mL), and sodium hydroxide (8 mg, 0.2 mmol) was added. The mixture was stirred at 25° C. for 15 minutes, concentrated, and washed with EA to obtain 30 mg of the product.

[0427] Molecular formula: C 27 H 27 F3N5NaO3S molecular weight: 581.6 LC-MS (M / e): 560.0 (M+H + -1Na + )

[0428] 1 H-NMR(400MHz,DMSO-d6)δ:7.74-7.63(m,3H),7.40-7.30(m,2H),5.11(s,1H),3. 20-3.00(m,8H),2.85(m,1H),1.45(m,4H),1.15-1.05(m,4H),0.30-0.20(m,4H).

[0429] Example 8: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-6-((2-hydroxyethyl)sulfonamide)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 9)

[0430]

[0431] 1. Preparation of 4,6-dichloronicotinic acid methyl ester (Int-31)

[0432] Dissolve 4,6-dichloronicotinic acid (Int-30, 10 g, 52 mmol) in DMF (100 mL), add potassium carbonate (14 g, 104 mmol) and iodomethane (7.4 g, 52 mmol) at 0°C, and react at 25°C for 1 hour. Add water to quench, filter, and dry the filter cake to obtain 7 g of the product, with a yield of 65.2%. 2. Preparation of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid methyl ester (Int-33)

[0433] Compound Int-31 (6.3 g, 31 mmol) was dissolved in DMF (60 mL), and 6-azaspiro[2.5]octane hydrochloride (8.6 g, 62 mmol) and potassium carbonate (4.6 g, 31 mmol) were added, and the reaction was carried out at 55°C for 3 hours. The reaction was completed. Water was added to quench the mixture, and EA was extracted twice. The concentrated residue was purified by silica gel column (EA:PE=30%) to obtain 6 g of the target compound, with a yield of 69.9%.

[0434] 3. Preparation of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Int-34)

[0435] Compound Int-33 (3 g, 11 mmol) was dissolved in THF / MeOH / H2O (30 mL / 10 mL / 10 mL), and lithium hydroxide (1.8 g, 44 mmol) was added, and the mixture was reacted at 60°C for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the pH was adjusted to 5-6 with 2M dilute HCl. The mixture was filtered and the filter cake was dried to obtain 2.6 g of the product with a yield of 91.2%.

[0436] 4. Preparation of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride (Int-35)

[0437] Compound Int-34 (1 g, 3.8 mmol) was dissolved in DCM (5 mL) and DMF (0.1 mL), and thionyl chloride (1.8 g, 15.2 mmol) was added at 0°C, and the reaction was continued for 30 minutes. After the reaction was completed, the reaction solution was concentrated and dried to obtain a crude product, which was directly used in the next step.

[0438] 5.6-Chloro-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Int-36)

[0439] 1-(3,3-Difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (850 mg, 3.8 mmol) was dissolved in DCM (30 mL), and DIPEA (2.0 g, 15.2 mmol) and compound Int-35 (crude, 3.8 mmol) were added, and the reaction was continued at 25°C for 1 hour until the reaction was completed. The concentrated residue was purified by silica gel column (EA:DCM=50%) to obtain 700 mg of the target compound, with a two-step yield of 39.0%.

[0440] 6. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-6-((2-hydroxyethyl)sulfonamide)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 9)

[0441] Compound Int-36 (180 mg, 0.38 mmol) and compound Int-8 (143 mg, 1.1 mmol) were dissolved in DMF (5 mL), and CuI (72 mg, 0.38 mmol) and (1R, 2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (54 mg, 0.38 mmol) and potassium phosphate (242 mg, 1.1 mmol), purged with nitrogen 3 times, and reacted at 130°C for 16 hours under nitrogen protection. After the reaction was completed, water was added to quench, extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 10: 1) to obtain a crude product, which was slurried with methanol to obtain 60 mg of the target compound, with a yield of 28.1%.

[0442] Molecular formula: C 25 H 29 F2N7O4S molecular weight: 561.2 LC-MS (M / e): 562.0 (M+H + )

[0443] 1 H-NMR(400MHz,DMSO-d6)δ:11.30-11.50(m,1H),8.05-8.35(m,4H),6.70(s,1H),5.18-5.28(m,1H ),4.78-7.90(m,1H),3.78(s,2H),3.00-3.20(m,6H),3.40-3.48(m,6H),1.58(s,4H),0.35(s,4H).

[0444] Example 9: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-5-((2-hydroxyethyl)sulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyridineamide (Compound 10)

[0445]

[0446] 1. Preparation of 5-bromo-3-fluoropicolinic acid methyl ester (Int-38)

[0447] 5-Bromo-3-fluoropicolinic acid (Int-37, 15.0 g, 68.2 mmol) was dissolved in DMF (100 mL), iodomethane (38.0 g, 267.6 mmol) and potassium carbonate (50.0 g, 361.8 mmol) were added, and the reaction was continued at 50°C for 3 hours. After the reaction was completed, the organic phase was extracted and concentrated with EA to obtain 14 g of the crude target product.

[0448] Preparation of 2.5-bromo-3-(6-azaspiro[2.5]octan-6-yl)picolinic acid methyl ester (Int-39)

[0449] Compound Int-38 (10.0 g, 42.7 mmol) was dissolved in DMF, potassium carbonate (24.0 g, 173.7 mmol) and compound Int-32 (7.5 g, 50.8 mmol) were added, and the reaction was completed at 80°C for 2 hours. After concentration, column chromatography (EA:PE=1:1) was performed to obtain 13.0 g of the target product with a yield of 59.0%.

[0450] Preparation of 3.5-bromo-3-(6-azaspiro[2.5]octan-6-yl)picolinic acid (Int-40)

[0451] Compound Int-39 (10.0 g, 30.7 mmol) was dissolved in methanol (70 mL) and water (70 mL), and lithium hydroxide (2.2 g, 92.0 mmol) was added. After stirring at 25 °C for 25 minutes, the mixture was concentrated, and the pH of the aqueous phase was adjusted to 7 with 4M HCl. The mixture was extracted with EA, and the organic phase was concentrated to obtain 8.0 g of the crude target compound.

[0452] Preparation of 4.5-bromo-3-(6-azaspiro[2.5]octan-6-yl)picolinoyl chloride (Int-41)

[0453] Compound Int-40 (6.0 g, crude product) was dissolved in DCM (70 mL), and thionyl chloride (20 mL) was added. After stirring at 0°C for 1 h, the mixture was concentrated to obtain 6.5 g of a crude product.

[0454] 5. Preparation of 5-bromo-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyridineamide (Int-42)

[0455] 1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (1.0 g, 4.5 mmol) and DIPEA (2.3 g, 17.8 mmol) were dissolved in DCM (50 mL), compound Int-41 (1.6 g, 4.9 mmol) was added, and the reaction was continued at 40° C. for 3 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (EA:PE=1:2) to obtain 1.1 g of the target compound with a yield of 47.7%.

[0456] 6. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-5-((2-hydroxyethyl)sulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyridineamide (Compound 10)

[0457] Compound Int-42 (250 mg, 0.48 mmol) and compound Int-8 (121 mg, 0.97 mmol) were dissolved in 1,4-dioxane (20 mL), Pd2(dba)3 (45 mg, 0.049 mmol), XantPhos (43 mg, 0.074 mmol) and cesium carbonate (470 mg, 1.4 mmol) were added, purged with nitrogen for 3 times, and reacted at 100°C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (DCM: methanol = 25: 1) to obtain 130 mg of the target compound with a yield of 47.9%.

[0458] Molecular formula: C 25 H 29 F2N7O4S molecular weight: 561.6 LC-MS (M / e): 562.1 (M+H + )

[0459] Example 9-1: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-5-((2-hydroxyethyl)sulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide disodium salt (Compound 10-1)

[0460] Compound 10 (30 mg, 0.053 mmol) was dissolved in methanol (5 mL), sodium hydroxide (5 mg, 0.13 mmol) was added, and the mixture was stirred at 25° C. for 25 minutes and concentrated to obtain 35 mg of the product.

[0461]

[0462] Molecular formula: C 25 H 27 F2N7Na2O4S molecular weight: 605.6 LC-MS (M / e): 562.1 (M+H + -2Na + )

[0463] 1 H-NMR(400MHz,DMSO-d6)δ:7.85-7.79(m,1H),7.65-7.56(m,1H),7.53(m,2H),6.83(s,1H),5.28-5. 17(m,1H),3.81-3.75(m,2H),3.52-2.90(m,8H),2.89-2.80(m,2H),1.39-1.30(m,4H),0.23(s,4H).

[0464] Example 10: Preparation of 6-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 11)

[0465]

[0466] Compound Int-36 (200 mg, 0.42 mmol) was dissolved in DMSO (10 mL), sodium cyclopropanesulfonate (108 mg, 0.84 mmol), potassium carbonate (23 mg, 0.17 mmol), CuI (16 mg, 0.084 mmol) and L-proline (9.7 mg, 0.084 mmol) were added, and the mixture was reacted at 140°C for 2 hours under nitrogen protection. The reaction was completed. Saturated sodium bicarbonate aqueous solution was added for quenching, EA was extracted, and the concentrated residue was purified by silica gel column (EA:PE=47%), EA was used for pulping, filtered, and spin-dried to obtain the target compound (100 mg, yield: 43.5%).

[0467] Molecular formula: C 26 H 28 F2N6O3S molecular weight: 542.2 LC-MS (M / e): 543.0 (M+H + )

[0468] 1H-NMR(400MHz,DMSO-d6)δ:11.32(s,1H),8.54(s,1H),8.00-8.40(m,3H),8.29(s,1H),7.46(s,1H ),5.20-5.30(m,1H),3.40-3.48(m,8H),2.99(s,4H),1.45(s,4H),1.00-1.10(m,4H),0.35(s,4H).

[0469] Example 11: Preparation of (5-(cyclopropylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)pyridinoyl)(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amide (Compound 12)

[0470]

[0471] Compound Int-42 (200 mg, 0.39 mmol) was dissolved in DMSO (8 mL), sodium cyclopropanesulfonate (111 mg, 0.77 mmol), potassium carbonate (10 mg, 0.072 mmol), CuI (20 mg, 0.10 mmol) and L-proline (15 mg, 0.13 mmol) were added, and microwave reaction was performed at 140°C for 1 hour under nitrogen protection. The reaction was completed. The mixture was extracted with water and EA, the organic phase was washed with water, and the residue was concentrated and purified by silica gel column (DCM: MeOH = 50: 1) to obtain 150 mg of the target compound, with a yield of 71.5%.

[0472] Molecular formula: C 26 H 28 F2N6O3S molecular weight: 542.6 LC-MS (M / e): 542.1 (M+H + )

[0473] Example 11-1: Preparation of (5-(cyclopropylsulfonyl)-3-(6-azaspiro[2.5]oct-6-yl)pyridinoyl)(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amide sodium salt (Compound 12-1)

[0474]

[0475] Compound 12 (60 mg, 0.11 mmol) was dissolved in methanol (7 mL), sodium hydroxide (6 mg, 0.15 mmol) was added, and the mixture was stirred at 25° C. for 25 minutes and concentrated to obtain 60 mg of the product.

[0476] Molecular formula: C 26 H 27F2N6NaO3S molecular weight: 564.6 LC-MS (M / e): 542.1 (M+H + )

[0477] 1 H-NMR(400MHz,DMSO-d6)δ:8.28(s,1H),7.78(s,1H),7.67-7.64(m,1H),7.48(s,1H),7.32-7.30(m,1H),5.20-5.07(m,1H),3 .55-3.35(m,4H),3.30-3.15(m,6H),3.15-3.05(m,2H),1.45-1.35(m,4H),1.35-1.15(m,2H),1.15-1.08(m,2H),0.30(s,4H).

[0478] Example 12: Preparation of 6-(cyclopropylsulfonyl)-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide and sodium salt (Compound 14, Compound 14-1)

[0479]

[0480] 1. Preparation of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride (Int-43)

[0481] Compound Int-34 (500 mg, 1.9 mmol) was dissolved in DCM (10 mL), and dichlorothionyl (669 mg, 5.6 mmol) was added and reacted for 2 h. After the reaction was completed, the reaction solution was concentrated and dried to obtain a crude product, which was directly used in the next step.

[0482] 2. Preparation of 6-chloro-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Int-45)

[0483] 3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine (compound Int-44, 428 mg, 1.9 mmol) was dissolved in DCM (30 mL), and DIPEA (980 mg, 7.6 mmol) and compound Int-43 (crude product) were added, and the reaction was continued at 50°C for 16 hours until the reaction was completed. The concentrated residue was purified by silica gel column (EA:PE = 0-50%) to obtain 70 mg of the target compound, with a two-step yield of 7.8%.

[0484] 3. Preparation of 6-(cyclopropylsulfonyl)-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 14)

[0485] Compound Int-45 (35 mg, 0.074 mmol) was dissolved in DMSO (10 mL), sodium cyclopropylsulfinate (19 mg, 0.15 mmol), potassium carbonate (4 mg, 0.03 mmol), CuI (3 mg, 0.015 mmol) and L-proline (2 mg, 0.015 mmol) were added, and the mixture was reacted at 140°C for 2 hours under nitrogen protection. The reaction was completed. Saturated sodium bicarbonate aqueous solution was added for quenching, EA was extracted, and the concentrated residue was purified by silica gel column (EA:PE=47%), EA was used for pulping, filtration was performed, and spin-dried to obtain 18 mg of the target compound, with a yield of 45%.

[0486] 4. Preparation of 6-(cyclopropylsulfonyl)-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide sodium salt (Compound 14-1)

[0487] Compound 14 (10 mg, 0.018 mmol) was dissolved in methanol (5 mL), and 0.054 M sodium methoxide methanol solution (352 uL, 0.019 mmol) was added. The mixture was reacted at 20° C. for 0.5 hour and concentrated to obtain 10 mg of the target compound. The yield was 98%.

[0488] Molecular formula: C 25 H 26 F2N7NaO3S molecular weight: 565.6 LC-MS (M / e): 544.2 (M-Na - +2H + )

[0489] 1 H-NMR(400MHz,DMSO-d6)δ:8.34(s,1H),8.25-8.05(m,1H),7.89(s,1H),7.26(s,1H),5.30 -5.20(m,1H),3.60-3.28(m,8H),2.95(s,1H),1.45(s,4H),1.00-1.10(m,4H),0.35(s,4H).

[0490] Example 13: Preparation of (5-(cyclopropylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)pyridinoyl)(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)amide and sodium salt (Compound 16, Compound 16-1)

[0491]

[0492] Preparation of 1.5-bromo-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide (Int-46)

[0493] Compound Int-44 (1.0 g, 4.4 mmol) and DIPEA (2.3 g, 17.8 mmol) were dissolved in 1,2-dichloroethane (50 mL), and compound Int-41 (1.6 g, 4.9 mmol) was added, and the reaction was continued at 50°C for 3 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (EA:PE=1:2) to obtain 1.1 g of the target compound, with a yield of 47.8%.

[0494] Preparation of 2.5-(cyclopropylsulfonyl)-N-(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyridineamide (Compound 16)

[0495] Compound Int-46 (200 mg, 0.39 mmol) was dissolved in DMSO (8 mL), sodium cyclopropylsulfinate (111 mg, 0.87 mmol), potassium carbonate (10 mg, 0.072 mmol), CuI (20 mg, 0.10 mmol) and L-proline (15 mg, 0.13 mmol) were added, and microwave reaction was performed at 140°C for 1 hour under nitrogen protection. The reaction was completed. The mixture was extracted with water and EA, the organic phase was washed with water, and the residue was concentrated and purified by silica gel column (DCM: MeOH = 50: 1) to obtain 150 mg of the target compound with a yield of 71.5%.

[0496] 3. Preparation of (5-(cyclopropylsulfonyl)-3-(6-azaspiro[2.5]oct-6-yl)pyridinoyl)(3-(3,3-difluorocyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)amide sodium salt (Compound 16-1)

[0497] Compound 16 (30 mg, 0.055 mmol) was dissolved in methanol (7 mL), sodium hydroxide (3 mg, 0.075 mmol) was added, and the mixture was stirred at 25° C. for 25 minutes and concentrated to obtain 33 mg of the product.

[0498] Molecular formula: C 25 H 26 F2N7NaO3S molecular weight: 565.2 LC-MS (M / e): 544.2 (M+H + -Na + )

[0499] 1 H-NMR(400MHz,DMSO-d6)δ:8.65-8.42(m,2H),8.25-8.01(brs,1H),7.87(s,1H),5.40-5.17(m,1H),3.55-3.35(m ,4H),3.30-3.15(m,4H),3.15-3.05(m,1H),1.55-1.35(m,4H),1.35-1.15(m,2H),1.15-1.08(m,2H),0.30(s,4H).

[0500] Example 14: Preparation of N-(4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide and its sodium salt (Compound 18, Compound 18-1)

[0501]

[0502] 1. Preparation of N-(4-bromo-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (Int-47)

[0503] 1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (450 mg, 1.8 mmol) was dissolved in DMF (10 mL), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (510 mg, 1.8 mmol), triethylamine (220 mg, 2.2 mmol) and HATU (700 mg, 1.8 mmol) were added, and the mixture was reacted at 25° C. for 1 hour until the reaction was completed. The concentrated residue was purified by silica gel column (EA:PE=30%), slurried with EA, filtered, and dried to obtain 600 mg of the target compound with a yield of 65.38%.

[0504] 2. Preparation of N-(4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide (Compound 18)

[0505] Compound Int-47 (150 mg, 0.29 mmol) was dissolved in DMSO (5 mL), and sodium cyclopropylsulfinate (60 mg, 0.47 mmol), potassium carbonate (50 mg), CuI (50 mg) and L-proline (50 mg) were added, and the mixture was reacted at 140°C in a microwave oven under nitrogen protection for 1 hour. The reaction was completed. Saturated sodium bicarbonate aqueous solution was added to quench the mixture, and EA was extracted. The residue was concentrated and purified by silica gel column (EA:PE=47%), EA was used for pulping, filtration was performed, and the target compound 130 mg was obtained by spin drying.

[0506] 3. Preparation of N-(4-(cyclopropylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide sodium salt (Compound 18-1)

[0507] Compound 18 (100 mg, 0.18 mmol) was dissolved in 20 mL of methanol, sodium hydroxide (9 mg) was added, and the mixture was reacted at 25° C. for 1 hour. After concentration, 105 mg of the product was obtained.

[0508] Molecular formula: C 27 H 28 F2N5O3SNa molecular weight: 563.6 LC-MS (M / e): 542.1 (M+H + )

[0509] 1 H-NMR(400MHz,DMSO-d6)δ:8.32-8.30(m,1H),8.21(s,1H),8.16-8.14(s,1H),7.93-7.91(m,1H),7.20-7. 18(m,2H),5.70-5.65(m,1H),3.43-3.15(m,9H),3.56-3.41(m,4H),1.08-0.98(m,4H),0.27-0.24(m,4H).

[0510] Example 15: Preparation of 4-(azetidin-3-ylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide hydrochloride (hydrochloride salt of compound 20, i.e., compound 20-1)

[0511]

[0512] tert-Butyl 3-((4-((1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (Int-48) (250 mg) was dissolved in DCM (5 mL), added to HCl / Dioxane (4 M, 5 mL), reacted at 25 °C for 1 h, and concentrated to obtain 220 mg of the product.

[0513] Molecular formula: C 27 H 31 F2N6O3SCl molecular weight: 593.1 LC-MS (M / e): 558.1 (M+H + )

[0514] 1 H-NMR(400MHz,DMSO-d6)δ:13.36(s,1H),9.73(s,1H),9.46(s,1H),8.35-8.33(m,2H),8.30-8.22(m,2H),7.92-7.86(m ,2H),5.27-5.26(m,1H),4.98-4.88(m,1H),4.20-4.18(m,4H),3.52-3.18(m,8H),1.87-1.78(m,4H),0.27-0.24(m,4H).

[0515] Example 16: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide and its disodium salt (Compound 22, Compound 22-1)

[0516]

[0517] 1. Preparation of 4-bromo-2-fluoro-6-(6-azaspiro[2.5]oct-6-yl)benzoyl chloride (Int-50)

[0518] 4-Bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzoic acid (Int-50, 1.9 g, 5.8 mmol) was dissolved in DCM (20 mL), and dichlorothionyl (1.4 g, 11.6 mmol) was added and reacted for 21 h. After the reaction was completed, the reaction solution was concentrated and dried to obtain 1.6 g, with a yield of 80.0%.

[0519] 2. Preparation of 4-bromo-N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-52)

[0520] 1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (Int-51, 224 mg, 1.0 mmol) was dissolved in DMF (50 mL), 60% NaH (120 mg, 3.0 mmol) was added, and the mixture was reacted at 0°C for 0.5 hours, and compound Int-50 (347 mg, 1.0 mmol) was added, and the reaction was continued at 50°C for 6 hours until the reaction was completed. The concentrated residue was purified by silica gel column (EA:PE=0-50%) to obtain 100 mg of the target compound, with a yield of 18.7%.

[0521] 3. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 22)

[0522] Compound Int-52 (100 mg, 0.2 mmol) and 2-hydroxyethane-1-sulfonamide (78 mg, 0.6 mmol) were dissolved in DMF (5 mL), and CuI (38 mg, 0.2 mmol), DMEDA (18 mg, 0.2 mmol) and potassium phosphate (127 mg, 0.6 mmol) were added, and the mixture was ventilated with nitrogen for 3 times, and reacted at 100° C. for 10 hours under nitrogen protection. After the reaction was completed, water was added to quench, and the mixture was extracted with water and EA. The organic phase was washed with water, concentrated, and purified by silica gel column chromatography (EA:PE=1:1) to obtain 60 mg, with a yield of 55.4%.

[0523] 4. Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)benzamide disodium salt (Compound 22-1)

[0524] Compound 23 (60 mg, 0.1 mmol) was dissolved in methanol (2 mL), sodium hydroxide (8 mg, 0.2 mmol) was added, and the mixture was reacted at 20° C. for 0.5 hour. The mixture was concentrated to obtain 64 mg of the target compound, with a yield of 99.1%.

[0525] Molecular formula: C 26 H 27 F3N6Na2O4S molecular weight: 622.6 LC-MS (M / e): 579.0 (M-2Na+ +3H + )

[0526] Example 17: Preparation of N-(3-(4,4-difluorocyclohexyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 25)

[0527]

[0528]

[0529] 1. Preparation of 3-bromo-N-(3,4-dimethoxybenzyl)pyrazolo[1,5-a]pyrimidine (Int-54)

[0530] Add 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (30 g, 129.04 mmol) to a three-necked flask, add dimethoxybenzylamine (21.58 g, 129.04 mmol), add THF (500 ml), and dropwise add triethylamine (26.12 g, 258.10 mmol). React at 40-45°C for 5 h, remove about half of the solvent by rotary evaporation, add heptane (500 ml) for slurrying, filter and dry to obtain 41.40 g of solid, with a yield of 88.6%.

[0531] 2. Preparation of 3-(4,4-difluorocyclohexyl-1-en-1-yl)-N-(3,4-dimethoxybenzyl)pyrazolo[1,5-a]pyrimidin-5-amine (Int-56)

[0532] Add compound Int-54 (7.00 g, 19.33 mmol) to a 500 ml three-necked flask, add 2-(4,4-difluorocyclohexyl-1-ene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int-55) (5.19 g, 21.26 mmol), add cesium carbonate (6.30 g, 19.33 mmol), Breatphos Pd G3 (700 mg), add dioxane (140 ml), and 20 ml of water. Nitrogen replacement protection, switch to oil bath at 80 ° C for 16 hours. The reaction liquid is subjected to column chromatography to obtain 4.40 g of the product with a yield of 56.9%.

[0533] 3. Preparation of 3-(4,4-difluorocyclohexyl)-N-(3,4-dimethoxybenzyl)-pyrazolo[1,5-a]pyrimidin-5-amine (Int-57)

[0534] Compound Int-56 (1.5 g, 3.75 mmol) was added to a 500 ml hydrogenation reactor, palladium carbon (500 mg) was added, and the mixture was stirred at 0.5 MPa for 2 days. The mixture was filtered and the filtrate was subjected to column chromatography to obtain 800 mg of the product with a yield of 53.1%.

[0535] 4. Preparation of 3-(4,4-difluorocyclohexyl)pyrazolo[1,5-a]pyrimidin-5-amine (Int-58)

[0536] Add compound Int-57 (750 mg, 1.86 mmol) and trifluoroacetic acid (10 ml) to a 50 ml single-mouth bottle, and stir to react for 2 hours. Concentrate the reaction solution to dryness, add MTBE (5 ml) to slurry, and filter to obtain 550 mg of crude product, which is directly used in the next step reaction.

[0537] 5. Preparation of N-(3-(4,4-difluorocyclohexyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-59)

[0538] Add Int-58 (360 mg of the crude product from the previous step) to a 100 ml single-mouth bottle, add THF (50 ml), add NaH (500 mg) and stir for 0.5 hours. Add compound Int-6 (500 mg, 1.33 mmol) and react for 3 hours, then drop water (1 ml) to quench the reaction. Column chromatography gave 340 mg of solid, with a two-step yield of 47.1%.

[0539] 6. Preparation of N-(3-(4,4-difluorocyclohexyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 25)

[0540] Add compound Int-59 (0.30 g, 0.51 mmol), hydroxysulfonamide (0.13 g, 1.04 mmol), CuI (0.19 g, 1.00 mmol), potassium phosphate (1.12 g, 5.28 mmol), DMEDA (0.17 g, 1.93 mmol), DMF (5 mL) to a 25 ml single-mouth bottle, and replace with nitrogen for protection. React at 100 ° C for 3 hours, and separate by column chromatography to obtain 28 mg of the product, with a yield of 9.38%.

[0541] Molecular formula: C 28 H 34 F2N6O4S molecular weight: 588.67 LC-MS (M / e): 589.3 (M+H + )

[0542] 1H-NMR(400MHz,DMSO-d6)δ:13.45(s,1H),10.25(s,1H),8.98(s,1H),8.07-7.94(m,3H),7.28(s,1H),7.13-7.05(m, 1H),4.98-4.85(m,1H),3.82-3.70(m,3H),3.30-3.36(m,2H),3.04-2.932.93-3.04(m,5H),2.20-2.00(m,4H),1.97 -1.70(m,4H),1.43-1.15(m,3H),0.37(m,4H).

[0543] Example 18: Preparation of 4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)-N-(3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzamide (Compound 26)

[0544]

[0545] 1. Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-N-(3,4-dimethoxybenzyl)pyrazolo[1,5-a]pyrimidin-5-amine (Int-61)

[0546] Add compound Int-54 (7.00 g, 19.33 mmol) to a 500 ml three-necked flask, add 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int-60) (4.47 g, 21.76 mmol), add cesium carbonate (6.30 g, 19.33 mmol), Breatphos Pd G3 (700 mg), add dioxane (140 ml) and water (20 ml). Nitrogen replacement protection, switch to oil bath, react at 80 ° C for 16 hours. The reaction liquid is subjected to column chromatography to obtain 6.10 g of the product with a yield of 86.1%.

[0547] 2. Preparation of N-(3,4-dimethoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-pyrazolo[1,5-a]pyrimidin-5-amine (Int-62)

[0548] Compound Int-61 (6.0 g, 16.37 mmol) was added to a 500 ml hydrogenation reactor, palladium carbon (1.8 g) was added, and the mixture was stirred and reacted for 2 days under a hydrogen atmosphere. The filtrate was filtered and column chromatography was performed to obtain 5.13 g of the product, with a yield of 85.0%.

[0549] 3. Preparation of 3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine (Int-63)

[0550] Add compound Int-62 (5.0 g, 13.57 mmol) and trifluoroacetic acid (30 ml) to a 50 ml single-mouth bottle, and stir to react for 2 hours. Concentrate the reaction solution to dryness, add MTBE (30 ml), and slurry filter to obtain 3.3 g of crude product, which is directly used in subsequent reactions.

[0551] 4. Preparation of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzamide (Int-64)

[0552] Add compound Int-63 (500 mg, crude product from the previous step) to a 250 ml single-mouth bottle, add THF (100 ml), add sodium hydride (800 mg, 60%, 20.00 mmol) and stir for 0.5 hours. Add compound Int-6 (800 mg, 2.13 mmol) and react for 3 hours, then drop 3 ml of water to quench the reaction. Column chromatography gave 380 mg of solid, with a two-step yield of 33.2%.

[0553] 5. Preparation of 4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)-N-(3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzamide (Compound 26)

[0554] Compound Int-64 (0.28 g, 502.3 mmol), hydroxysulfonamide (0.13 g, 1.04 mmol), CuI (0.19 g, 1.0 mmol), potassium phosphate (1.12 g, 5.28 mmol), DMEDA (0.17 g, 1.93 mmol) and DMF (5 ml) were added to a 25 ml single-mouth bottle, and nitrogen was replaced for protection. The reaction was carried out at 100 ° C for 3 hours, and 28 mg of the product was separated by column chromatography, with a yield of 10.05%.

[0555] Molecular formula: C 27 H 34 N6O5S molecular weight: 554.67 LC-MS (M / e): 555.2 (M+H + )

[0556] 1H-NMR(400MHz,DMSO-d6)δ:13.62(s 1H),10.28(s 1H),8.97(m 1H),8.08(m 1H),7.98(m,1H),7.93(m 1H),7.65(s,1H),7.14-7.05(m,1H),4.88-4.75(m,1H),4.01-3.90(m,2H),3.85-3.74(m,3H ),3.20(m,2H),2.87-3.12(m,5H),1.96(m,1H),1.86(m,4H),1.85-1.43(m,4H),0.38(m,4H).

[0557] Example 19: Preparation of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-(methylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 28)

[0558]

[0559] N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Int-65) (100 mg, 0.18 mmol) and methylsulfonamide (19 mg, 0.20 mmol) were dissolved in DMF (5 mL), CuI (17 mg), DMEDA (28 mg) and potassium phosphate (20 mg) were added, purged with nitrogen for 3 times, and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench, extracted with water and EA, the organic phase was washed with water, concentrated, and purified by silica gel column chromatography (DCM: methanol = 25:1) to obtain 50 mg of the target compound, with a yield of 53.1%.

[0560] Molecular formula: C 25 H 28 F2N6O3S molecular weight: 530.6 LC-MS (M / e): 531.2 (M+H + )

[0561] 1 H-NMR (400MHz, DMSO-d6) δ: 13.87 (s, 1H), 10.31 (s, 1H), 8.29-8.09 (m, 4H), 7.28 (s, 1H) ),7.15(m,1H),5.26-5.24(m,1H),3.38-3.01(m,11H),2.10-1.61(m,4H),0.41(m,4H).

[0562] In addition, the following compounds were prepared using the same or similar methods as in the above examples:

[0563]

[0564] The KIF18A inhibitor and its application provided by the present invention are introduced 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 used to help understand the method of the present invention and its central idea. It should be pointed out that for ordinary technicians in this field, without departing from the principles of the present invention, the present invention can also be improved and modified in several ways, and these improvements and modifications also fall within the protection of the claims of the present invention.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, wherein: in, X 1 Select from N or CR 1a ; X 2 Selected from CR 2a R 2b or NR 2c ; X 3 Select from N or CR 3a ; X 4 Select from N or CR 4a ; X 5 Select from N or CR 5a ; Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; L is selected from -NR-C(O)-, -C(O)-NR'-, -NR-S(O)-, -S(O)-NR'-, -NR-S(O)2- or -S(O)2-NR'-; R, R' at each occurrence 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 1 Selected from the following groups: Each Q1 is independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, haloC 1-6 Alkoxy, or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 substituents Q2; the substituents Q2 are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 1a , R 3a , R 4a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 2a , R 2b , R 2c Each occurrence is independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano or the following groups which are optionally substituted with 1 to 3 substituents Q3: 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, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -phenyl, -(CH2) m -5-6 membered heteroaryl, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group; The Q3 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 m and n is independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has a structure represented by general formula (II), in, Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; R 1 Selected from Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclobutyl; Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 4a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 5a , R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; m and n are independently selected from 0, 1 or 2.

3. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has a structure represented by general formula (II), in, Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; R 1 Selected from Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 2c Selected from -(CH2) optionally substituted with 1-3 Q3 m - cyclopropyl; Each Q3 is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 4a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 5a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 6a , R 7a is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; m and n are independently selected from 0, 1 or 2.

4. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has a structure represented by general formula (III), in, Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; R 1 Selected from Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 1a , R 4a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group; The Q3 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 m and n is independently selected from 0, 1 or 2.

5. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has a structure represented by general formula (IV), in, Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; R 1 Selected from Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 4a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group; The Q3 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 m and n is independently selected from 0, 1 or 2.

6. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has a structure represented by general formula (V), in, Y1 is selected from N or CR 6a ; Y2 is selected from N or CR 7a ; R 1 Selected from Each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 1a , R 5a , R 6a , R 7a Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 2c is selected from hydrogen, halogen or the following groups optionally substituted by 1-3 Q3: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Alkyl-OC 1-2 Alkylene, halogenated C 1-3 Alkyl-OC 1-2 Alkylene, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocyclic group; The Q3 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 m and n is independently selected from 0, 1 or 2.

7. A compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, having the following structure:

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

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, its ester or its stereoisomer, 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 a disease mediated by KIF18A or a related disease; wherein, The disease or related disease mediated by KIF18A is selected from cancer or benign tumor; the cancer or benign tumor is selected from 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 is selected from small cell lung cancer and non-small cell lung cancer; the blood tumor is selected from leukemia, lymphoma, myeloma; the brain cancer is selected from glioma, neuroblastoma, astrocytoma, meningioma.

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