KIF18A inhibitor and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a KIF18A inhibitor compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and a preparation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof. 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

KIF18A inhibitors and uses thereof Technical Field

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

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

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

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

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

[0006] Summary of the Invention

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

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

[0009] in,

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

[0011] X 2 With X 3 The connection between them is single bond or double bond;

[0012] When X 2 With X 3 When the connection mode between is single key, X 2 、X 3 are independently selected from N or C; when X 2 With X 3 When the connection between them is a double bond, X 2 、X 3 All are C;

[0013] Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl;

[0014] R 1is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered bridged heterocyclyl, optionally substituted with one or more substituents Q2;

[0015] R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, -(L) optionally substituted with one or more substituents Q3 m -C 1-6 Alkyl, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkynyl, -(L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group;

[0016] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6Alkyl)amino, -C(O)-NH2, C 1-6 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, optionally substituted by 1-4 substituents q, wherein the substituents q are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0017] Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -;

[0018] Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group;

[0019] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0020] Each m and n is independently an integer of 0-6.

[0021] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0022] X 1 、X 4 are independently selected from N or CR a ;

[0023] X 2 With X 3 The connection between them is single bond or double bond;

[0024] When X 2 With X 3 When the connection mode between is single key, X 2 、X 3 are independently selected from N or C; when X 2 With X 3 When the connection between them is a double bond, X 2 、X 3 All are C;

[0025] Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl;

[0026] R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered bridged heterocyclyl, optionally substituted with one or more substituents Q2;

[0027] R 2 、R 3 、R 4 、R 6 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, -(L) optionally substituted with one or more substituents Q3 m -C 1-6 Alkyl, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6Alkynyl, -(L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group; and R 2 、R 3 、R 4 、R 6 At least one is not hydrogen;

[0028] R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q3 m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl;

[0029] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, -C(O)-NH2, C 1-6 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, optionally substituted by 1-4 substituents q, wherein the substituents q are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0030] Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -;

[0031] Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group;

[0032] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6alkyl;

[0033] Each m and n is independently an integer of 0-6.

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

[0035] X 1 、X 4 are independently selected from N or CR a ;

[0036] X 2 With X 3 The connection between them is single bond or double bond;

[0037] When X 2 With X 3 When the connection mode between is single key, X 2 、X 3 are independently selected from N or C; when X 2 With X 3 When the connection between them is a double bond, X 2 、X 3 All are C;

[0038] Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl;

[0039] R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered bridged heterocyclyl, optionally substituted with one or more substituents Q2;

[0040] R 2 、R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, -(L) optionally substituted with one or more substituents Q3 m -C 1-6 Alkyl, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkynyl, -(L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group;

[0041] R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q3 m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl;

[0042] R 6 Selected from -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(Rc )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl;

[0043] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, -C(O)-NH2, C 1-6 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, optionally substituted by 1-4 substituents q, wherein the substituents q are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0044] Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -;

[0045] Each R a , each R a1, each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group;

[0046] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0047] Each m and n is independently an integer of 0-6.

[0048] 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 At least one of them is N.

[0049] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 、X 2 、X 3 、X 4 There are at least two N.

[0050] 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 .

[0051] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 Selected from N.

[0052] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 Selected from C.

[0053] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 2 Selected from N.

[0054] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 Selected from C.

[0055] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 3 Selected from N.

[0056] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 Selected from CR a .

[0057] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 Selected from N.

[0058] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl.

[0059] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl.

[0060] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0061] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-6 membered cycloalkyl, a 5-6 membered nitrogen-containing heterocyclic group or a 5-6 membered nitrogen-containing heteroaryl group.

[0062] In certain embodiments, the compounds shown in the preceding schemes, their pharmaceutically acceptable salts, their esters, or their stereoisomers, wherein ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl.

[0063] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Ring A is selected from dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

[0064] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0065] Each R a , each R 1 , each Q1, each n is defined as described in any of the above technical solutions.

[0066] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0067] Each R a , each R 1 , every Q 1 , the definition of each n is as described in any of the above technical solutions.

[0068] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0069] Each R a , each R 1 , each Q1, each n is defined as described in any of the above technical solutions.

[0070] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0071] Each R a , each R 1 , every Q 1 , the definition of each n is as described in any of the above technical solutions.

[0072] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0073] Each R a , each R 1 , every Q 1 , the definition of each n is as described in any of the above technical solutions.

[0074] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,

[0075] Each R a , each R 1 , every Q 1 , the definition of each n is as described in any of the above technical solutions.

[0076] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, 7-11 membered spirocyclyl, and 7-11 membered spiroheterocyclyl, which are optionally substituted with 1-4 substituents Q2.

[0077] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl or 5-6 membered heteroaryl, which are optionally substituted with 1-3 substituents Q2.

[0078] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from a 3-6 membered cycloalkyl group, a 3-6 membered nitrogen-containing heterocyclic group, a phenyl group, a 7-8 membered spiroheterocyclic group or a 5-6 membered nitrogen-containing heteroaryl group, which is optionally substituted by 1-3 substituents Q2.

[0079] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from a 3-6 membered cycloalkyl group, a 7-8 membered spiroheterocyclyl group or a 3-6 membered nitrogen-containing heterocyclyl group which is optionally substituted by 1-3 substituents Q2.

[0080] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, and 7-8 membered spiroheterocyclyl, which are optionally substituted with 1 to 3 substituents Q2.

[0081] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from a 4- to 6-membered heterocyclic group optionally substituted by 1 to 3 substituents Q2, preferably a 4- to 6-membered nitrogen-containing heterocyclic group.

[0082] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 is selected from 5-6 membered cycloalkyl groups optionally substituted by 1 to 3 substituents Q2.

[0083] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 It is selected from a 7-8 membered spiro heterocyclic group optionally substituted by 1 to 3 substituents Q2, preferably a 7-8 membered nitrogen-containing spiro heterocyclic group.

[0084] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidinyl, oxetanyl, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophene, tetrahydrothiophene, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, pyranyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 2-piperidonyl,

[0085] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 1 is selected from dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 2-piperidonyl,

[0086] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 、R 5 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl.

[0087] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R2 、R 5 are independently selected from hydrogen, optionally substituted by 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl.

[0088] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 、R 5 Each is independently selected from hydrogen, a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl optionally substituted with 1 to 3 substituents Q3.

[0089] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 、R 5 Each is independently selected from hydrogen, a 5-6 membered nitrogen-containing heterocyclic group or a 7-9 membered nitrogen-containing spiro heterocyclic group optionally substituted by 1 to 3 substituents Q3.

[0090] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from an 8-membered nitrogen-containing spiro heterocyclic group optionally substituted by 1-3 substituents Q3; R 2 Selected from hydrogen.

[0091] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 、R 5 Each is independently selected from the following structures which are hydrogen, optionally substituted by 1-3 substituents Q3:

[0092] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q3 m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L)m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl;

[0093] R 2 -(L) is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl.

[0094] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 Selected from -(L) optionally substituted with 1 to 4 substituents Q3 m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl;

[0095] R 2 -(L) is selected from hydrogen, optionally substituted by 1 to 4 substituents Q3 m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclic group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl.

[0096] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from 5-6 membered heterocyclic group, 7-10 membered spiroheterocyclic group, which are optionally substituted by 1-3 substituents Q3; 2 Selected from hydrogen.

[0097] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 R is selected from a 5-6 membered nitrogen-containing heterocyclic group or a 7-9 membered nitrogen-containing spiro heterocyclic group optionally substituted by 1-3 substituents Q3; 2 Selected from hydrogen.

[0098] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, cyano, optionally substituted with 1-4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl.

[0099] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0100] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 、R 4 Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0101] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each L is independently selected from -C(O)-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -.

[0102] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each L is independently selected from -S(O)2-, -NR c -、-CR a1 R b -.

[0103] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl.

[0104] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from -C(O)N(Rc )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl.

[0105] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from -N(R c )S(O)2-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -N(R c )-C 1-6 Alkyl, -N(R c )-C 1-6 alkyl.

[0106] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from -N(H)S(O)2-C optionally substituted by 1-3 substituents Q3 1-4 Alkyl, -S(O)2N(H)-C 1-4 Alkyl, -S(O)2-C 1-4Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(H)S(O)2-3-6 membered cycloalkyl, -S(O)2N(H)-3-6 membered cycloalkyl, -N(H)-C 1-4 Alkyl, -N(H)-C 1-4 alkyl.

[0107] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from the following structures:

[0108] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 Selected from the following structures:

[0109] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0110] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino.

[0111] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0112] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q1, each Q2, and each Q3 are independently selected from fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methylamino, ethylamino, and dimethylamino.

[0113] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from halogen, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0114] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0115] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0116] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, haloC 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0117] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b Each of the groups is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0118] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0119] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R a , each R a1 , each R b are each independently selected from hydrogen.

[0120] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 alkyl.

[0121] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R cEach is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0122] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently an integer of 0-4.

[0123] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently 0, 1, 2, or 3.

[0124] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently an integer of 0-4.

[0125] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently 0, 1, 2, or 3.

[0126] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl;

[0127] R 1 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, 7-11 membered spirocyclyl, 7-11 membered spiroheterocyclyl, optionally substituted by 1-4 substituents Q2;

[0128] R 2 、R 5 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl;

[0129] R 3 、R 4are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl;

[0130] R 6 Selected from -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl;

[0131] Each R a , each R a1 , each Rb are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0132] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0133] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino;

[0134] Each of m and n is independently an integer of 0-4.

[0135] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0136] Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0137] R 1 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl, optionally substituted by 1-3 substituents Q2;

[0138] R 2 、R 5 are independently selected from hydrogen, optionally substituted by 1 to 3 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L)m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl; R 2 、R 5 Not simultaneously hydrogen;

[0139] R 6 Selected from -N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl.

[0140] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0141] Ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl;

[0142] R 1 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl or 5-6 membered heteroaryl, which are optionally substituted with 1-3 substituents Q2;

[0143] R 2 、R 5Each is independently selected from hydrogen, a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl optionally substituted with 1-3 substituents Q3;

[0144] R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0145] R 6 Selected from -N(R c )S(O)2-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -N(R c )-C 1-6 alkyl;

[0146] Each R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0147] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0148] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0149] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (I-1),

[0150] Wherein, Y1 and Y2 are independently selected from N or CH;

[0151] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a , each Q1, n is defined as described in any of the above schemes.

[0152] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (I-1'),

[0153] Wherein, Y1 and Y2 are independently selected from N or CH;

[0154] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 , each R a , each Q1, n is defined as described in any of the above schemes.

[0155] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (I-2),

[0156] Wherein, Y1 and Y2 are independently selected from N or CH;

[0157] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a , each Q1, n is defined as described in any of the above schemes.

[0158] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II),

[0159] Where n is 0, 1, or 2;

[0160] R 1 、R 2 、R 3 、R 4、R 5 、R 6 , the definition of each Q1 is as described in any of the above schemes.

[0161] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II'),

[0162] Among them, X 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , each R a , n, each Q1 is defined as described in any of the above schemes.

[0163] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof has a structure shown in formula (II'), wherein n is 0, 1, or 2; X 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , each R a , n, each Q1 is defined as described in any of the above schemes.

[0164] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof has a structure shown in formula (II'), wherein X 1 Select N or CR a ;

[0165] R 1 is selected from a 3-6 membered cycloalkyl group, a 7-8 membered spiroheterocyclyl group or a 3-6 membered nitrogen-containing heterocyclyl group optionally substituted by 1-3 substituents Q2;

[0166] R 2 、R 5 Each is independently selected from hydrogen, a 5-6 membered nitrogen-containing heterocyclic group or a 7-9 membered nitrogen-containing spiroheterocyclic group optionally substituted by 1-3 substituents Q3;

[0167] R 3 、R 4 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0168] R 6 -NHS(O)2-C optionally substituted with 1-4 substituents Q3 1-6 Alkyl, -S(O)2NH-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -NH-C 1-6 alkyl;

[0169] Each R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, haloC 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0170] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, carboxyl C 1-4 alkyl;

[0171] n is 0, 1, or 2.

[0172] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 、R 5 Not hydrogen at the same time.

[0173] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II-1) or (II-1'),

[0174] Among them, each X 6 selected from N or CH;

[0175] Each R 1 , each R 2 , each R 3 , each R 4 , each R 6 、R a , each Q1, each Q2, each Q3, and each n are defined as described in any of the aforementioned schemes.

[0176] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II-2) or formula (II-2'),

[0177] wherein each L1 is independently selected from NR c , O, S or CR a1 R b ; Each X 5 , each X 6 are independently selected from N or CH;

[0178] p is an integer selected from 0 to 2;

[0179] R 2 、R 3 、R 4 、R 6 、R a , each R a1 , each R b , each Q1, each Q2, each Q3, and each n are defined as described in any of the aforementioned schemes.

[0180] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II-3) or formula (II-3'),

[0181] wherein each L1 is independently selected from -NH-, -O-, -S- or -CH2-; each p is selected from an integer from 0 to 2;

[0182] Each R 6 、R a , each Q1, each Q2, each Q3, and each n are defined as described in any of the aforementioned schemes.

[0183] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0184] Selected from the following structures:

[0185] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (III) or formula (III'),

[0186] Among them, X 5 、X 6 are independently selected from N or CH;

[0187] Each R 2 , each R 3 , each R 4 , each R 6 、R a , each Q1, each Q2, each Q3, and each n are defined as described in any of the aforementioned schemes.

[0188] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (III) or formula (III'),

[0189] Among them, each X 5 , each X 6 Each independently is N;

[0190] Each R 2 , each R 3 , each R 4 are each independently hydrogen;

[0191] R 6 Selected from the following structures:

[0192] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0193] Each n is 0, 1, or 2.

[0194] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (II-2) or formula (II-2'),

[0195] Among them, X 5 、X 6 are independently selected from N or CH;

[0196] Each L1 is independently selected from NH, O or CH2;

[0197] R 2 、R 3 、R 4 are independently selected from hydrogen or C 1-6 alkyl;

[0198] R 6 Selected from the following structures:

[0199] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0200] p and n are independently 0, 1, and 2, respectively.

[0201] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV) or formula (IV'),

[0202] Each R 1 , each R 2 , each R 3 , each R 4 , each R 5 , each R 6 、R a , each X 2 , each X 3 , each X 4 , each Q1, each Q2, each Q3, and each n are defined as described in any of the aforementioned schemes.

[0203] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-1) or formula (IV-1'),

[0204] Each R 1 , each R 6 , each R a , each X 2 , each X 3 , each X 4 , each Q1, each Q2, each Q3, and n are defined as described in any of the aforementioned schemes.

[0205] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-2) or formula (IV-2'),

[0206] Each R 1 、R a , each X2 , each X 3 , each X 4 , each Q1, each Q2, and each n are defined as described in any of the aforementioned schemes.

[0207] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-3) or formula (IV-3'),

[0208] Each X 2 , each X 3 , each X 4 , each Q1, each n, each R a is as defined in any of the preceding schemes.

[0209] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0210] Selected from the following structures,

[0211] R 1 is selected from dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 2-piperidonyl,

[0212] R 2 selected from hydrogen;

[0213] R 5 Selected from the following structures optionally substituted by 1-3 substituents Q3:

[0214] Each R a 、R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0215] R 6 Selected from the following structures:

[0216] Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0217] In certain embodiments, the compound of the present invention, its pharmaceutically acceptable salt, ester or stereoisomer thereof has a structure represented by the general formula (I'),

[0218] Among them, X 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 5 、R 6 , each R a , the definition of each Q1 is as described in any of the above technical solutions.

[0219] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in the general formula (I'-1),

[0220] Wherein, Y1 and Y2 are independently selected from N or CH;

[0221] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a , each Q1, n is defined as described in any of the above schemes.

[0222] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (I'-1),

[0223] R 1 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl or 5-6 membered heteroaryl, which are optionally substituted with 1-3 substituents Q2;

[0224] R 2 、R 5 R is independently selected from hydrogen, 5-6 membered heterocyclic group or 7-10 membered spiroheterocyclic group optionally substituted by 1-3 substituents Q3; 2 、R 5 Not simultaneously hydrogen;

[0225] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0226] R 6 Selected from -N(R c )S(O)2-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -N(R c )-C 1-6 alkyl;

[0227] Each R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0228] Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0229] Each Q1 is selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0230] n is 0, 1, or 2.

[0231] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in the general formula (I'-2),

[0232] wherein Y2 is selected from N or CH;

[0233] R 1 is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 7-8 membered spiroheterocyclyl, optionally substituted by 1-3 substituents Q2;

[0234] R 2 Selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 alkoxy;

[0235] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0236] R 6 Selected from -N(H)S(O)2-C optionally substituted by 1-3 substituents Q3 1-4 Alkyl, -S(O)2N(H)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(H)S(O)2-3-6 membered cycloalkyl, -S(O)2N(H)-3-6 membered cycloalkyl, -N(H)-C 1-4 Alkyl, -N(H)-C 1-4 alkyl;

[0237] R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0238] Each Q1 is selected from halogen, carboxyl, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, carboxyl C 1-4 alkyl;

[0239] n is 0, 1, or 2.

[0240] In some embodiments of the present invention, the structure of the provided compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof is as follows:

[0241] The present invention also provides a pharmaceutical composition comprising a compound represented by the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), and general formula (IV-3'), a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

[0242] The second therapeutic agent of the present invention includes but is not limited to growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotics, angiogenesis inhibitors, biological response modifiers, antihormones, and anticancer drugs.

[0243] The present invention also provides a pharmaceutical preparation containing the compounds represented by the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), and general formula (IV-3'), their pharmaceutically acceptable salts, esters or stereoisomers, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is in any dosage form that is clinically or pharmaceutically acceptable.

[0244] In some embodiments of the present invention, the pharmaceutical preparations described above can be administered to patients or subjects requiring such treatment orally, parenterally, rectally, or transpulmonaryly. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid preparations such as tablets, capsules, pills, granules, or oral liquid preparations such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, lubricants, and the like can be added to these oral preparations. For parenteral administration, the pharmaceutical preparations described above can also be formulated into injectables, including injections, sterile powders for injection, and concentrated solutions for injection. Injectables can be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories. For transpulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays.

[0245] Available pharmaceutical carrier and / or diluent in pharmaceutical composition of the present invention or pharmaceutical preparation can be any conventional carrier and / or diluent in pharmaceutical preparation field, and the selection of specific carrier and / or diluent will depend on the mode of administration or disease type and state that are used to treat specific patient.The preparation method of the suitable pharmaceutical composition that is used for specific administration mode is fully within the knowledge scope of pharmaceutical field technicians.For example, pharmaceutical carrier and / or diluent can comprise the conventional solvent, diluent, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, adhesive, lubricant, stabilizer, hydrating agent, emulsification accelerator, buffer, absorbent, coloring agent, ion exchanger, releasing agent, coating agent, flavoring agent and antioxidant etc. in pharmaceutical composition.If desired, flavoring agent, preservative and sweetening agent etc. can also be added in pharmaceutical composition.

[0246] The present invention also provides the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (I V'), compounds represented by general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), and general formula (IV-3'), their pharmaceutically acceptable salts, esters, or stereoisomers thereof, the aforementioned pharmaceutical preparations, or the aforementioned pharmaceutical compositions in the preparation of drugs 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.

[0247] The present invention also provides the use of the compounds represented by the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), and general formula (IV-3'), their pharmaceutically acceptable salts, esters, or stereoisomers thereof, the aforementioned pharmaceutical preparations, or the aforementioned pharmaceutical compositions 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.

[0248] The present invention also provides a method for treating a disease, which comprises administering to a patient in need thereof a therapeutically effective amount of the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), Compounds represented by general formula (III'), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), and general formula (IV-3'), their pharmaceutically acceptable salts, esters, or stereoisomers thereof, the aforementioned pharmaceutical preparations, or the aforementioned pharmaceutical compositions, 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.

[0249] The cancer or benign tumor includes but is not limited to breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, 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.

[0250] The present invention provides a method for preparing the above-mentioned compound, but is not limited to the following method. The reaction equation of the preparation method is as follows:

[0251] Step 1: Dissolve the compound of formula (II'-2) in a suitable solvent (e.g., dichloromethane), add the compound of formula (II'-1) and a basic substance (e.g., N,N-diisopropylethylamine) in an organic solvent (e.g., dichloromethane), react for 1-5 hours, and obtain the compound of formula II'-3 of the present invention by a suitable method (e.g., silica gel column chromatography).

[0252] Step 2: Dissolve the compound of formula (II'-3) in a suitable solvent (eg N,N-dimethylformamide), add a catalyst (eg cuprous halide) and an alkaline substance (eg potassium phosphate, N,N-diisopropylethylamine, etc.) for reaction, and add R 6 -H, react under nitrogen protection for 1-5 hours, and obtain the compound of general formula II' of the present invention after post-treatment.

[0253] Post-treatment includes, but is not limited to, quenching with water, extraction with an organic solvent (such as ethyl acetate), concentration, column chromatography, or a combination of several of these methods.

[0254] The above preparation method can be simply summarized as follows: reacting the compound of formula (II'-1) with the compound of formula (II'-2) to obtain the compound of formula (II'-3); reacting the compound of formula (II'-3) with R 6 -H reaction to obtain a compound of formula II'.

[0255] Wherein, X is a halogen; X 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , each R a , n, each Q1 is defined as described in any of the above schemes.

[0256] The present invention also provides intermediates for preparing compounds represented by general formula (I) to general formula (IV-3'), pharmaceutically acceptable salts, esters, or stereoisomers thereof, which have the following structural formula:

[0257] wherein each X is independently a halogen; each X 1 , each R 1 , each R 2 , each R 3 , each R 4 , each R 5 , each R 6 , each R a , each n, and each Q1 are defined as described in any of the aforementioned schemes.

[0258] The present invention also provides intermediates for preparing compounds represented by general formula (I) to general formula (IV-3'), pharmaceutically acceptable salts, esters, or stereoisomers thereof, which have the following structural formula:

[0259] wherein each X is independently a halogen; each X 1 , each R 1 , each R 2 , each R 3 , each R 4 , each R 6 , each R a , each n, and each Q1 are defined as described in any of the aforementioned schemes.

[0260] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0261] In this application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. In the event that the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

[0262] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0263] The term "halo" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogen atoms, which may be the same or different. "Halogen" is as defined above.

[0264] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-5 Alkyl", "C 1-4 Alkyl", "C 1-3 Alkyl", "C 1-2 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 2-4 Alkyl", "C 2-3 Alkyl", "C 3-6 Alkyl", "C 3-5 Alkyl", "C 3-4 Alkyl", "C 4-6 Alkyl", "C 4-5 Alkyl", "C 5-6Specific 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.

[0265] The "C 1-6 "Alkylene" refers to the above-mentioned C 1-6 The group formed by removing a hydrogen atom from an alkyl group includes, for example, "C 1-5 Alkylene", "C 1-4 Alkylene", "C 1-3 Alkylene", "C 1-2 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene", "C 2-4 Alkylene", "C 2-3 Alkylene", "C 3-6 Alkylene", "C 3-5 Alkylene", "C 3-4 Alkylene", "C 4-6 Alkylene", "C 4-5 Alkylene", "C 5-6 Specific examples include but are not limited to methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The "C 1-4 "Alkylene" refers to C 1-6 Specific examples of the alkylene group include those containing 1 to 4 carbon atoms.

[0266] The "C 2-6 "Alkenyl" refers to a linear, branched or cyclic alkenyl group with 2 to 6 carbon atoms containing at least one double bond, including, for example, "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl -1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, and the like.

[0267] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group with 2 to 8 carbon atoms containing a triple bond, including, for example, "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, and the like.

[0268] 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-, C1-6 Alkyl-S(O)2-, C 1-6 Alkyl-S(O)2-NH-, C 1-6 Alkyl-NH-S(O)2-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-OC(O)-formed groups, wherein "C 1-6 "Alkyl" is as defined above.

[0269] The “C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Alkyl aminoacyl, C 1-4 Alkyl amido, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylcarbonyl, C 1-4 "Alkoxycarbonyl" refers to a C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 Alkyl) 2-N-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-C(O)-NH-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S(O)2-NH-, C 1-4 Alkyl-NH-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-OC(O)-formed groups, wherein "C 1-4 "Alkyl" is as defined above.

[0270] The "halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, halogenated C 1-6 "Alkoxy" refers to one or more (e.g. 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, carboxyl groups, etc. 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by the hydrogen atoms in an alkoxy group.

[0271] The "halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C1-4 Alkyl, halogenated C 1-4 "Alkoxy" refers to one or more (e.g. 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups substituted with C 1-4 Alkyl, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0272] The "3-12 membered cycloalkyl group" described in the present invention refers to a saturated or partially saturated non-aromatic cyclic alkyl group containing 3-12 carbon atoms, including "monocyclic alkyl" and "condensed cyclic alkyl".

[0273] The "monocycloalkyl" mentioned in the present invention refers to a saturated or partially saturated monocyclic alkyl group without aromaticity, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl" "cycloalkyl", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "4-7 membered saturated cycloalkyl", "4-8 membered saturated cycloalkyl", "5-8 membered saturated cycloalkyl", "5-7 membered saturated cycloalkyl", "5-6 membered saturated cycloalkyl", "3-6 membered partially saturated cycloalkyl", "4-7 membered partially saturated cycloalkyl", "4-8 membered partially saturated cycloalkyl", "5-8 membered partially saturated cycloalkyl", "5-7 membered partially saturated cycloalkyl", "5-6 membered partially saturated cycloalkyl", etc. Specific examples of the “3-8 membered saturated cycloalkyl” include, but are not limited to, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropane, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0274] The "condensed cycloalkyl" mentioned in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms. One of the rings in the condensed ring may be aromatic, but the condensed ring as a whole does not have aromaticity. The condensed ring may be in the form of: 5-6-membered cycloalkyl and 5-6-membered cycloalkyl, benzo 5-6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl, etc. Examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0275] The "3-12 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic or condensed ring cyclic group containing at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and 3-12 ring atoms, and having no aromaticity, wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. The "3-12 membered heterocyclic group" of the present invention includes "3-12 membered saturated heterocyclic groups" and "3-12 membered partially saturated heterocyclic groups." Preferably, the "3-12 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-12 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 "3-12 membered heterocyclic group" of the present invention contains 1-2 nitrogen atoms. The “3-12 membered heterocyclic group” is preferably a “3-10 membered heterocyclic group”, “3-8 membered heterocyclic group”, “4-8 membered heterocyclic group”, “3-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “4-6 membered heterocyclic group”, “4-6 membered nitrogen-containing heterocyclic group”, “5-6 membered heterocyclic group”, “5-6 membered saturated heterocyclic group” and the like.Specific examples of “3-12 membered heterocyclic group” include, but are not limited to, aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxinadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, 2-piperidonyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H- 1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, pyrrolidinylcyclopropyl, cyclopentylaziridinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl yl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridothiazolidinyl, pyridopiperdinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidothiazolidinyl, pyrimidopiperdinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3 ]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl, 4,6-dihydro-1H- Thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, and the like.

[0276] The "6-10 membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl groups" and "8-10 membered condensed ring aryl groups".

[0277] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0278] The "8-10 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms. It is preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl.

[0279] The "5-12 membered heteroaryl group" described in the present invention refers to an aromatic cyclic group containing 5-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom), and can include, for example, a 5-12 membered nitrogen-containing heteroaryl group, a 5-12 membered oxygen-containing heteroaryl group, or a 5-12 membered sulfur-containing heteroaryl group. It includes "5-8 membered single heteroaryl groups" and "8-10 membered fused heteroaryl groups."

[0280] The "5-8 membered monoheteroaryl" of the present invention refers to a monocyclic cyclic group having aromaticity and containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms, or sulfur atoms) in the ring structure may be oxo-substituted. The "5-8 membered monoheteroaryl" includes, for example, "5-7 membered monoheteroaryl", "5-6 membered monoheteroaryl", "5-6 membered nitrogen-containing monoheteroaryl", "5 membered nitrogen-containing monoheteroaryl", etc. Specific examples of “5-8 membered monocyclic heteroaryl” include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The "5- to 6-membered heteroaryl" refers to a specific example of a 5- to 8-membered heteroaryl containing 5 to 6 ring atoms.

[0281] The "8-10 membered fused heteroaryl" herein refers to an unsaturated aromatic cyclic structure containing 8-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0282] The "5-12 membered bridged ring group" of the present invention refers to a structure containing 5-12 carbon atoms formed by any two rings sharing two atoms that are not directly connected. The "5-12 membered bridged ring" includes a 5-12 membered saturated bridged ring group and a 5-12 membered partially saturated bridged ring group. Preferred are a 5-10 membered bridged ring group, a 5-8 membered bridged ring group, a 5-10 membered saturated bridged ring group, a 5-8 membered saturated bridged ring group, a 6-10 membered saturated bridged ring group, and a 7-12 membered partially saturated bridged ring group. Specific examples include but are not limited to

[0283] The "5-12-membered bridged heterocyclic group" of the present invention refers to a 5-12-membered bridged heterocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and also includes the case where the carbon atoms, nitrogen atoms, and sulfur atoms may be oxo-substituted. Preferably, the 5-10-membered bridged heterocyclic group or the 5-8-membered bridged heterocyclic group is used. Specific examples include, but are not limited to:

[0284] The "5-12 membered spirocyclyl" of the present invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing one atom. It comprises a 5-12 membered saturated spirocyclyl and a 5-12 membered partially saturated spirocyclyl, including, for example, a "5-10 membered saturated spirocyclyl", "5-10 membered unsaturated spirocyclyl", "5-8 membered spirocyclyl", "5-8 membered saturated spirocyclyl", "5-8 membered unsaturated spirocyclyl", "6-8 membered spirocyclyl", "7-11 membered spirocyclyl", "7-10 membered spirocyclyl", "7-9 membered spirocyclyl", "8-10 membered spirocyclyl", "8-11 membered spirocyclyl", and specific examples of the 5-12 membered saturated spirocyclyl include but are not limited to: A group formed by replacing any substitutable hydrogen atom with a cyclic structure such as 5-12. A 5-12 membered partially saturated spirocyclic group refers to a cyclic group in which at least one ring is unsaturated. Specific examples include but are not limited to: A group formed by replacing any substitutable hydrogen atom with a cyclic structure.

[0285] The "5-12 membered spiro heterocyclyl" of the present invention refers to a 5-12 membered spiro heterocyclyl in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, or N, preferably 1 to 3 heteroatoms, and includes a situation where the carbon atom, nitrogen atom, and sulfur atom can be oxoed. Including, for example, a 5-10 membered spiro heterocyclyl, a 5-8 membered spiro heterocyclyl, a 5-6 membered spiro heterocyclyl, a 7-12 membered spiro heterocyclyl, a 7-11 membered spiro heterocyclyl, a 7-11 membered nitrogen-containing spiro heterocyclyl, a 7-10 membered spiro heterocyclyl, a 7-10 membered nitrogen-containing spiro heterocyclyl, a 7-9 membered spiro heterocyclyl, a 7-9 membered nitrogen-containing spiro heterocyclyl, a 7-8 membered spiro heterocyclyl, a 7-8 membered nitrogen-containing spiro heterocyclyl, and an 8 membered nitrogen-containing spiro heterocyclyl. Specific examples include, but are not limited to:

[0286] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0287] The "pharmaceutically acceptable salts" described in the present invention refer to pharmaceutically acceptable acid and base addition salts, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, salts formed with acidic amino acids or basic amino acids, etc.

[0288] The "ester" of the present invention refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes esters that are easily decomposed in the human body to leave the parent compound (the compound of formula (I)) or its salt. The "ester" of the present invention can be selected from the following groups: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected from, for example, C 1-20 Straight-chain or branched alkyl, C 1-12 Straight-chain or branched alkyl, C 1-8 Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g. methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (such as benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); and (4) mono-, di-, or triphosphates, etc.; (5) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl, C 1-12 Straight-chain or branched alkyl, C 1-8 Straight-chain or branched alkyl, C 1-6 Straight-chain or branched alkyl (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g. methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (such as benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C 6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0289] As used herein, "stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. Compounds of the present invention may have asymmetric centers, each of which independently gives rise to two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. Compounds of the present invention that contain olefinic double bonds include cis- and trans-isomers, unless otherwise specified. Compounds of the present invention may exist as tautomers (a type of functional group isomer) that have different points of hydrogen attachment due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and their mixtures are included within the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis- and trans-isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds are included within the scope of the present invention.

[0290] As used herein, a "therapeutically effective amount" refers to an amount of the aforementioned compound, pharmaceutical formulation, or pharmaceutical composition that, when administered to a patient, at least alleviates the symptoms of the patient's condition. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances, including, but not limited to, the specific condition being treated, the severity of the condition, the patient's physical condition and health, and the route of administration. Skilled medical practitioners can readily determine the appropriate amount using methods known in the medical field.

[0291] Advantageous Effects of the Invention

[0292] (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;

[0293] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0294] (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;

[0295] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0296] (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.

[0297] The following experiments further illustrate the beneficial effects of the compounds provided in the examples of the present invention, but this should not be understood as meaning that the compounds provided in the examples of the present invention only have the following beneficial effects.

[0298] Experimental Example 1 In vitro enzymatic activity of the compounds of the present invention

[0299] Test samples: some of the compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0300] Experimental reagents:

[0301] Experimental methods:

[0302] 1. Compound dilution

[0303] 1) The compound of the present invention was prepared in DMSO to 10 mM as a test stock solution.

[0304] 2) The test stock solution was diluted 3-fold to 10 concentrations, with the highest concentration being 10 mM.

[0305] 3) The final concentrations of the test compounds were 10000 nM, 3333.3 nM, 1111.1 nM, 370.4 nM, 123.5 nM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, and 0.51 nM.

[0306] 2. Enzyme reaction experiment

[0307] 1) Use an Echo 650 to transfer 0.025 μL of compound dilution to each well of a 384-well assay plate, with each column containing 2 replicates.

[0308] 2) Add 2.5 μL of enzyme working solution to a 384-well assay plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 10 minutes.

[0309] 3) Add 2.5 μL of ATP working solution and incubate at 25°C for 60 minutes.

[0310] 4) Add 4 μL of ADP-Glo ​​working solution and incubate at 25°C for 40 minutes.

[0311] 5) Add 8 μL of detection working solution and incubate at 25°C for 40 minutes.

[0312] 3. Result detection

[0313] 1) Read the chemiluminescent signal on the BMG HTS high-throughput drug screening multifunctional microplate reader.

[0314] 2) Collect data.

[0315] 4. Data Analysis

[0316] The inhibition rate (%inh) was calculated using the following formula:

[0317] Test compound inhibition rate (%inh) = 100*(ave High control-cpd well) / (ave High control-ave Low control)

[0318] Wherein, ave High control represents: the luminescent signal intensity of the positive control well without adding the compound;

[0319] Ave Low control indicates the luminescent signal intensity of the negative control well without enzyme addition;

[0320] Cpd well means: represents the luminescence signal intensity of the test compound;

[0321] IC calculation using XLfit 50 ,

[0322] Experimental results:

[0323] Table 1 Inhibitory activity of the compounds of the present invention on KIF18A

[0324] In addition to the compounds in Table 1, the IC of compound 10 on KIF18A inhibitory activity 50 The value is between 50nM and 500nM. From the above experimental results, it can be seen that the compound of the present invention can effectively inhibit the activity of KIF18A and is an effective KIF18A inhibitor.

[0325] Experimental Example 2 In vitro cytological activity of the compounds of the present invention

[0326] Test samples: some of the compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0327] The cell lines used in the following experiments are as follows:

[0328] OVCAR3: TP53-mutated human ovarian cancer cells

[0329] Experimental method (CelltiterGlo assay)

[0330] 1. Cell Preparation

[0331] 1.1 Cell culture:

[0332] All cells were adherent cells. The culture medium for OVCAR3 cells was RPMI Medium 1640 + 20% FBS + 1% PS. The cells were tested in the logarithmic growth phase.

[0333] 1.2 Preparation of cell suspension:

[0334] Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Adjust the concentration to the appropriate concentration and add 90 μL of the cell suspension to each well of a 96-well plate.

[0335] Table 2 Number of cells seeded

[0336] 2. Preparation of test compounds

[0337] 2.1 Prepare DMSO stock solution of the test compound. The concentration of the stock solution of the test compound is 10 mM.

[0338] 2.2 Preparation of test compound working stock solution

[0339] A 10 mM stock solution of the test compound was first diluted with DMSO to 0.123 mM, followed by a 1.5-fold serial dilution series for a total of nine concentrations. 2 μL of each DMSO-diluted compound was then added to 198 μL of culture medium to create the test compound working stock solution (compound concentration was 10 times the final concentration, with a maximum concentration of 123 nM).

[0340] 2.3 Compound treatment

[0341] 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.

[0342] The final concentrations of the test compounds were: 123 nM, 82.3 nM, 54.8 nM, 36.6 nM, 24.4 nM, 16.3 nM, 10.9 nM, 7.2 nM, 4.5 nM.

[0343] 2.4 Control well setting

[0344] Solvent control: 0.1% DMSO.

[0345] Blank control: culture medium

[0346] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 4 days.

[0347] 3. Detection

[0348] Thaw CTG reagent and equilibrate a 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Glo assay kit) to each well, shake on a shaker for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal using a multifunctional microplate reader.

[0349] 4. Data Processing

[0350] 1) Inhibition rate (%) = 1-(test substance well reading - blank control well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0351] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0352] Experimental results and conclusions

[0353] IC of the inhibitory activity of the compounds of the present invention against OVCAR3 50 The values ​​are indicated by A for 1nM to 100nM, B for 100nM to 500nM, and C for 500nM to 1000nM.

[0354] Table 3 In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0355] As shown in Table 3, the compounds of the present invention can effectively inhibit the proliferation of OVCAR3 cells, indicating that the compounds of the present invention have clinical application potential in treating cancerous diseases with TP53 mutations.

[0356] Experimental Example 3 In vitro cytological activity of the compounds of the present invention

[0357] Test samples: some of the compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0358] The cell lines used in the following experiments are as follows:

[0359] OVCAR3: human ovarian cancer cells with TP53 mutation; MDA-MB-157: human breast cancer cells with TP53 mutation

[0360] Experimental method (CelltiterGlo assay)

[0361] 1. Cell Preparation

[0362] 1.1 Cell culture:

[0363] 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.

[0364] 1.2 Preparation of cell suspension:

[0365] Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Adjust the concentration to the appropriate concentration and add 90 μL of the cell suspension to each well of a 96-well plate.

[0366] Table 4. Cell seeding number

[0367] 2. Preparation of test compounds

[0368] 2.1 Prepare DMSO stock solution of the test compound. The concentration of the stock solution of the test compound is 10 mM.

[0369] 2.2 Preparation of test compound working stock solution

[0370] The test compound stock solution was 10 mM and serially diluted 3-fold for a total of 9 concentrations. 2 μL of each DMSO-diluted compound was then added to 198 μL of culture medium to prepare the test compound working stock solution (compound concentration was 10 times the final concentration, with a maximum concentration of 100 μM).

[0371] 2.3 Compound treatment

[0372] 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.

[0373] The final concentrations of the test compounds were: 10 μM, 3.33 μM, 1.11 μM, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.57 nM, 1.52 nM.

[0374] 2.4 Control well setting

[0375] Solvent control: 0.1% DMSO.

[0376] Blank control: culture medium

[0377] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 4 days.

[0378] 3. Detection

[0379] Thaw CTG reagent and equilibrate a 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Glo assay kit) to each well, shake on a shaker for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal using a multifunctional microplate reader.

[0380] 4. Data Processing

[0381] 1) Inhibition rate (%) = 1-(test substance well reading - blank control well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0382] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0383] Experimental results and conclusions

[0384] IC of the inhibitory activity of the compounds of the present invention against OVCAR3 50 Value, 1nM~100nM is represented by A, 100nM~500nM is represented by B, 500nM~1000nM is represented by C; IC of the inhibitory activity of the compound of the present invention on MDA-MB-157 50The values ​​are indicated by A for 1nM to 100nM, B for 100nM to 500nM, and C for 500nM to 1000nM.

[0385] Table 5. In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0386] It is shown 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.

[0387] Experimental Example 4 Pharmacokinetics of the Compounds of the Invention in Mice

[0388] Test sample: Compound of the present invention, homemade, its chemical name and preparation method can be found in the preparation examples of each compound.

[0389] Test animals: female mice, 6 mice / administration route / compound.

[0390] 1. Preparation of test solution:

[0391] Preparation method of blank solvent (1): weigh 28g HP-β-CD (hydroxypropyl-β-cyclodextrin), add appropriate amount of water for injection to dissolve, then dilute to 100mL with water for injection, vortex mix, and obtain 28% HP-β-CD.

[0392] Preparation method of blank solvent (2): Weigh 20g HPC (hydroxypropyl cellulose), slowly add it to 500mL of stirred purified water, then add 1mL of Tween 80, stir until clear and transparent, adjust the volume to 1000mL, and stir evenly to obtain 2% HPC + 0.1% Tween 80.

[0393] IV (intravenous push) administration:

[0394] An appropriate amount of the compound of the present invention was weighed, DMA (N,N-dimethylacetamide) was added, and the solution was dissolved by ultrasonic vortexing. Kolliphor HS15 (polyethylene glycol-15-hydroxystearate) was then added and vortexed to mix. Finally, DPBS (Dulbecco's phosphate buffered saline) was added and vortexed to mix to prepare a 1 mg / mL clear solution, which was used as the IV dosing solution for the test compound.

[0395] PO (oral) administration:

[0396] An appropriate amount of the example compound of the present invention was weighed and placed in a tissue grinder. Blank solvent (2) was added and ground uniformly at a speed of 1000 rpm to prepare a 1 mg / mL or 3 mg / mL suspension solution, which was used as the PO administration solution for the test compound.

[0397] 2. Experimental methods

[0398] The IV dose was 5 mg / kg, the concentration was 1 mg / mL, and the volume was 5 mL / kg.

[0399] The PO dose is 30 mg / kg at a concentration of 3 mg / mL in a volume of 10 mL / kg. Alternatively, the PO dose is 10 mg / kg at a concentration of 1 mg / mL in a volume of 10 mL / kg.

[0400] Blood collection time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration. Blood was collected as shown in the following table:

[0401] At each time point, approximately 50 μL of whole blood was collected from the inner canthus of the eye and placed in an anticoagulant tube containing EDTA-K2 anticoagulant. The blood was centrifuged at 8000 rpm for 6 min at 4°C to obtain plasma samples, which were then frozen at -80°C until analysis.

[0402] 3. Plasma sample analysis

[0403] The protein precipitation method was used: 20 μL of plasma sample was taken, 200 μL of internal standard (acetonitrile solution containing 200 ng / mL of tolbutamide) was added, and the sample was vortexed for 10 minutes, followed by centrifugation at 4000 rpm for 20 minutes. 100 μL of the supernatant was taken, and 100 μL of water was added. After vortexing for 3 minutes, the drug concentration in the plasma was analyzed by LC-MS / MS.

[0404] 4. Experimental results and conclusions

[0405] The test results show that the compound of the present invention has good pharmacokinetic properties, a low clearance rate, and a high exposure and bioavailability. DETAILED DESCRIPTION

[0406] The technical solutions of the present invention are described below with reference to specific embodiments. The embodiments described are only some, not all, of the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0407] The abbreviations used in the following experiments have the following meanings:

[0408] Xphos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd(dppf)Cl2: Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; RuphosPdG3: Methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); DIPEA: N,N-diisopropylethylamine; PPTS: Pyridine p-toluenesulfonate

[0409] Example 1 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (Compound 1)

[0410] (1) Preparation of 6,8-dichloroimidazo[1,2-a]pyrazine

[0411] Chloroacetaldehyde (7.2 g, 36.7 mmol, 40% aqueous solution) was added to 3,5-dichloropyrazin-2-amine (3.0 g, 18.3 mmol) in DMF (40 mL) and allowed to react at 100°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and poured into water. Extraction was performed three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the ethyl acetate was removed under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (2.8 g, yield: 81.4%).

[0412] (2) Preparation of 6-chloro-8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazine

[0413] 6,8-Dichloroimidazo[1,2-a]pyrazine (2.8 g, 14.9 mmol), 4,4-difluoropiperidine (2.0 g, 16.5 mmol), DIPEA (5.8 g, 44.9 mmol), and NMP (8 mL) were added to a microwave oven and reacted at 100°C for 50 minutes. After completion of the reaction, the mixture was cooled to room temperature and poured into water. Extraction was performed three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the ethyl acetate was removed under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:2) to obtain the title compound (3.4 g, yield: 83.7%).

[0414] (3) Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamate

[0415] A mixture of 6-chloro-8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazine (1.2 g, 4.4 mmol), BocNH2 (1.0 g, 8.8 mmol), RuphosPdG3 (368 mg, 0.44 mmol), and cesium carbonate (2.9 g, 8.8 mmol) in 1,4-dioxane (20 mL) was reacted at 100°C under nitrogen for 8 hours. After completion, the product was purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (1.5 g, 96.4% yield).

[0416] (4) Preparation of 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-amine

[0417] Add 20 mL of hydrochloric acid in ethyl acetate to tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamate (850 mg, 2.4 mmol) in ethyl acetate (10 mL) at 30°C and allow to react for 3 hours. After completion of the reaction, remove the solvent under reduced pressure and proceed directly to the next step.

[0418] (5) Preparation of 2-fluoro-4-iodobenzoyl chloride

[0419] DMF (0.1 mL) was added to a solution of 2-fluoro-4-iodobenzoic acid (1.3 g, 4.9 mmol) and oxalyl chloride (1.2 g, 9.4 mmol) in dichloromethane (40 mL) at 0°C and the reaction was continued for 1 hour. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0420] (6) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-2-fluoro-4-iodobenzamide

[0421] A solution of 2-fluoro-4-iodobenzoyl chloride (crude product from the previous step) in dichloromethane (100 mL) was added dropwise to 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-amine (crude product from the fourth step) and DIPEA (3.0 g, 23.2 mmol) in dichloromethane (20 mL) at 0°C. The reaction was continued for 3 hours. After completion, the reaction was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:5) to obtain the title compound (400 mg, three-step yield: 33.2%).

[0422] (7) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0423] To a solution of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-2-fluoro-4-iodobenzamide (380 mg, 0.76 mmol) in dimethyl sulfoxide (15 mL) were added potassium carbonate (318 mg, 2.3 mmol) and 6-azaspiro[2.5]octane hydrochloride (221 mg, 1.5 mmol). The mixture was reacted at 100°C for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, and concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 1:5) to afford the title compound (220 mg, 49.0% yield).

[0424] (8) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0425] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (220 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cuprous iodide (70 mg, 0.37 mmol), N-methylglycine (33 mg, 0.37 mmol) and potassium phosphate (383 mg, 1.8 mmol) were added. The mixture was reacted at 50 ° C for 5 minutes. After adding 2-hydroxyethane-1-sulfonamide (94 mg, 0.75 mmol), the mixture was placed at 100 ° C for 2 hours under nitrogen protection. After the reaction was completed, water was added to quench the reaction, and the residue was extracted with ethyl acetate. The residue was concentrated and purified by silica gel column (ethyl acetate:petroleum ether=1:1) and reverse phase column (80% CH3OH / H2O) to obtain the title compound (45 mg, yield: 20.5%).

[0426] Molecular formula: C 27 H 33 F2N7O4S molecular weight: 589.7 LC-MS (M / e): 590.3 (M+H + )

[0427] 1H-NMR(400MHz,DMSO-d6)δ:12.88(s,1H),8.83(s,1H),8.08(m,2H),7.55(m,1H),7.27(m,1H),7.12(m, 1H),4.42(m,4H),3.84(m,2H),3.33(m,2H),3.14(m,4H),2.11(m,4H),1.98-1.67(m,5H),0.57(m,4H).

[0428] Example 2 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 3)

[0429] (1) Preparation of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine

[0430] Dissolve 3,5-dibromopyrazin-2-amine (5 g, 20 mmol), 1-bromo-2,2-dimethoxypropane (5.5 g, 30 mmol), and PPTS (503 mg, 2 mmol) in isopropanol (50 mL) and react at 70°C for 16 hours. After completion, cool to room temperature, adjust the pH to 8-9 with triethylamine, and spin dry. The residue is purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (2.6 g, yield: 44.5%).

[0431] (2) Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazine

[0432] 6,8-Dibromo-2-methylimidazo[1,2-a]pyrazine (1.2 g, 4.1 mmol), 4,4-difluoropiperidine (977 mg, 6.2 mmol), and DIPEA (1.6 g, 12.3 mmol) were dissolved in NMP (10 mL) and reacted at 100°C for 1 h. After completion, the reaction mixture was cooled to room temperature and poured into water. Extraction was performed three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the ethyl acetate was removed under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (1.3 g, yield: 95.7%).

[0433] (3) Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamate

[0434] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazine (1.2 g, 3.6 mmol), BocNH2 (1.3 g, 11.1 mmol), RuphosPdG3 (301 mg, 0.36 mmol), and cesium carbonate (4.7 g, 14.4 mmol) were dissolved in 1,4-dioxane (50 mL) and reacted at 100°C under nitrogen for 3 hours. After completion of the reaction, the mixture was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (1.2 g, yield: 90.7%).

[0435] (4) Preparation of 8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-amine

[0436] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamate (1.2 g, 3.3 mmol) in DCM (10 mL), add TFA (3 mL), and react at 25°C for 3 hours. After completion of the reaction, remove the solvent under reduced pressure, adjust the pH to 8-9 with saturated sodium bicarbonate aqueous solution, extract with DCM, and spin dry the organic phase to obtain 800 mg of the product in a yield of 90.5%.

[0437] (5) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0438] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude, 2.0 mmol) in dichloromethane (10 mL) at 0°C was added potassium phosphate (425 mg, 2.0 mmol) dropwise. Then, 8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-amine (536 mg, 2 mmol) and DIPEA (774 mg, 6.0 mmol) in dichloromethane (20 mL) were added dropwise. The reaction was continued at 25°C for 1 hour. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (800 mg, yield: 66.0%).

[0439] (6) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0440] N-(8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (63 mg, 0.33 mmol), N-methylglycine (59 mg, 0.66 mmol), and potassium phosphate (280 mg, 1.32 mmol) were added and reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (124 mg, 0.99 mmol) was added and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion, the reaction was quenched with water, filtered, and the filter cake was slurried with ethyl acetate to obtain the title compound (19 mg, yield: 9.5%).

[0441] Molecular formula: C 28 H 35 F2N7O4S molecular weight: 603.7 LC-MS (M / e): 604.2 (M+H + )

[0442] 1 H-NMR(400MHz, DMSO-d6+D2O)δ:12.89(s,1H),8.72(s,1H),8.02-8.10(m,1H),7.78(s,1H),7.26(s,1H),7.09-7.12(m,1H),4.28 -4.40(m,4H),3.70-3.80(m,2H),3.30-3.40(m,2H),2.97(s,4H),2.32(s,3H),2.00-2.20(m,4H),1.60-1.90(m,4H),0.39(s,4H).

[0443] Example 3 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 5)

[0444] 1. Preparation of (3,5-dichloropyrazin-2-yl)formamide

[0445] 3,5-Dichloropyrazine-2-cyanopropane (9.6 g, 55.2 mmol) was added to acetic acid (120 mL), followed by the addition of Raney nickel (1.90 g). The reaction mixture was replaced with hydrogen three times and allowed to react at 50°C under a hydrogen atmosphere for 18 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 99:1) to obtain the title compound (3.5 g, yield: 35.6%).

[0446] 2. Preparation of 6,8-dichloroimidazole[1,5-a]pyrazine

[0447] Anhydrous formic acid (20 ml) was added to the reaction flask, and acetic anhydride (10 ml) was added dropwise at 0°C for 1.5 h. At the same time, (3,5-dichloropyrazin-2-yl)formamide (2.5 g, 14.0 mmol) and DIEA (4.5 g, 34.8 mmol) were dissolved in DCM (20 ml) and slowly added dropwise to the reaction system for 1 h. The mixture was first concentrated, and ethyl acetate was added to the crude product, which was washed with saturated sodium bicarbonate. The liquids were separated, and the organic phase was concentrated. Phosphorus oxychloride (20 ml) was added, and the temperature was raised to 100°C for 1 h. The temperature was lowered and concentrated, and the product was slurried with MTBE to obtain 2.10 g of the product with a yield of 79.5%.

[0448] 3. Preparation of 6-chloro-8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazine

[0449] 6,8-Dichloroimidazole [1,5-a] pyrazine (2.1 g, 11.2 mmol), 4,4-difluoropiperidine (2.1 g, 13.4 mmol), DIPEA (7.2 g, 56.0 mmol) and NMP (25 mL) were added to a single-necked flask and reacted at 100 ° C for 1.5 h. After the reaction was completed, the mixture was cooled to room temperature and poured into water. The mixture was slurried and filtered, and the filter cake was dried to obtain the product (1.7 g, yield: 55.6%).

[0450] 4. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)carbamate

[0451] 6-Chloro-8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazine (1.4 g, 5.13 mmol), BocNH2 (1.2 g, 10.26 mmol), RuphosPdG3 (427 mg, 0.51 mmol), and cesium carbonate (5.0 g, 15.39 mmol) in 1,4-dioxane (60 mL) were reacted at 100°C under nitrogen for 8 hours. After completion of the reaction, the product was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (1.3 g, yield: 71.7%).

[0452] 5. Preparation of 8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-amine

[0453] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)carbamate (1.1 g, 3.1 mmol) in DCM (10 mL) at 30°C and add trifluoroacetic acid (10 mL) dropwise. Allow to react for 3 hours. After completion of the reaction, remove the solvent under reduced pressure and proceed directly to the next step.

[0454] 6. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0455] DMF (0.1 mL) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (667 mg, 1.87 mmol) and oxalyl chloride (475 mg, 3.74 mmol) in dichloromethane (20 mL) at 0°C and the reaction was continued for 1 hour. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0456] 7. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide

[0457] A solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude product from the previous step) in dichloromethane (10 mL) was added dropwise to 8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-amine (crude product from the fourth step) and DIPEA (2.0 g, 15.6 mmol) in dichloromethane (10 mL) at 0°C. The reaction was continued for 3 hours. After completion of the reaction, the product was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:2) to obtain the title compound (50 mg, 2.7% yield over three steps).

[0458] 8. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0459] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,5-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide (50 mg, 0.08 mol) was dissolved in DMAC (5 mL). Cuprous iodide (15 mg, 0.08 mmol), N-methylglycine (7 mg, 0.08 mmol), and potassium phosphate (85 mg, 0.40 mmol) were added. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (20 mg, 0.16 mmol) was added, and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, and concentrated, purified by silica gel column (ethyl acetate:petroleum ether = 1:2) and reverse phase column (100% CH3OH / H2O) to obtain the title compound (3 mg, yield: 6.3%).

[0460] Molecular formula: C 27 H 33 F2N7O4S molecular weight: 589.66 LC-MS (M / e): 590.3 (M+H + )

[0461] 1 H-NMR(400MHz, CDCl3-d6)δ:12.83(s,1H),8.75(s,1H),8.27-8.25(m,1H),8.10(m,1H),7.65(m,1H),7.35-7.29(m,1H),7 .11-7.08(m,1H),4.17(m,2H),4.03(m,4H),3.51(m,2H),3.37(m,2H),3.08(m,4H),2.21(m,4H),1.25(m,4H),0.42(m,4H).

[0462] Example 4 Preparation of N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 7)

[0463] (1) Preparation of 1,4,6-triaminopyrimidine-2(1H)-thione

[0464] Malononitrile (10.0 g, 0.15 mol) was dissolved in an ethanolic solution of sodium ethoxide (20% wt 76.5 g, 0.23 mol). Hydrazinethioamide (13.8 g, 0.15 mol) was added and allowed to react at 25°C for 16 hours. Upon completion of the reaction, a large amount of solid precipitated, which was filtered and dried to afford the title compound (9.6 g, 40.3% yield).

[0465] (2) Preparation of 7-amino-[1,2,4]triazolo[1,5-c]pyrimidine-5-thiol

[0466] Dissolve 1,4,6-triaminopyrimidine-2(1H)-thione (9.6 g, 61.1 mmol) in formic acid (160 mL) and react at 100°C for 16 hours. After completion of the reaction, concentrate the mixture and add purified water to precipitate a large amount of solid. Filter and spin dry to obtain the title compound (5.5 g, yield: 53.9%).

[0467] (3) Preparation of 5-(methylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine

[0468] Dissolve 7-amino-[1,2,4]triazolo[1,5-c]pyrimidine-5-thiol (2.2 g, 131 mmol) in N,N-dimethylformamide (25 mL), add iodomethane (1.7 g, 1.2 mmol), and potassium carbonate (5.4 g, 39 mmol). React at 25°C for 2 hours. After completion of the reaction, add purified water, extract twice with ethyl acetate, wash once with water, and concentrate to obtain the title compound (2.0 g, yield: 84.2%).

[0469] (4) Preparation of 5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine

[0470] 5-(Methylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine (2.0 g, 10 mmol) was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (85%) (4.1 g, 20 mmol) was added at 0°C. The mixture was allowed to react at 25°C for 1 hour, followed by the addition of N,N-diisopropylethylamine (3.9 g, 30 mmol) and 4,4-difluoropiperidine hydrochloride (1.7 g, 11 mmol). The reaction was continued at 25°C for 16 hours, and purified water was added. The mixture was extracted with dichloromethane and purified by column chromatography (ethyl acetate / n-heptane: 90%) to afford 325 mg of the title compound in a yield of 12.8%.

[0471] (5) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0472] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (840 mg, 2.4 mmol) in dichloromethane (10 mL), add N,N-dimethylformamide (0.1 mL), and then add dimethyl sulfoxide (428 mg, 5.5 mmol) at 0°C. React at 25°C for 0.5 h. After completion of the reaction, concentrate to dryness and use in the next step (1.1 g crude product).

[0473] (6) Preparation of N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0474] 5-(4,4-Difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine (300 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), and N,N-isopropylethylamine (464 mg, 3.6 mmol) was added dropwise to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (1.1 g, crude) in dichloromethane (10 mL) and potassium phosphate (254 mg, 1.2 mmol). The mixture was allowed to react at 25°C for 1 hour. After completion, the reaction was quenched with water, extracted with dichloromethane, and purified on a silica gel column (ethyl acetate:n-heptane = 32%) to afford 190 mg of the title compound, with a two-step yield of 13.3%.

[0475] (7) Preparation of N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-4-(2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0476] N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (190 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (61 mg, 0.32 mmol), N-methylglycine (57 mg, 0.64 mmol) and potassium phosphate (271 mg, 1.28 mmol) were added. The mixture was reacted at 50 ° C for 5 minutes, and 2-hydroxyethane-1-sulfonamide (120 mg, 0.96 mmol) was added. The mixture was placed at 100 ° C for 2 hours under nitrogen protection. After the reaction was completed, water was added to quench the reaction, and the residue was extracted with ethyl acetate. The residue was concentrated and purified on a silica gel column (ethyl acetate:n-heptane = 80%) to obtain 20 mg of a crude product. The target compound (2 mg, yield: 1.1%) was purified by high pressure column chromatography (acetonitrile / water: 35%).

[0477] Molecular formula: C 26 H 32 F2N8O4S molecular weight: 590.65 LC-MS (M / e): 591.0 (M+H + )

[0478] 1H-NMR(400MHz,DMSO-d6)δ:13.38(s,1H),10.32(s,1H),8.42(s,1H),8.0(d,1H),7.92(s,1H),7.19(s,1H),7.14(d,1H),4.01-4.24 (m,4H),3.60-3.78(m,2H),3.25-3.42(m,2H),3.00(m,4H),2.50-2.67(m,4H),2.21-2.33(m,2H),1.46-1.73(m,2H),0.422(m,4H).

[0479] Example 5 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide (Compound 8)

[0480] (1) Preparation of N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine

[0481] Dissolve 2-chloro-3-hydrazinopyrazine (5.0 g, 35 mmol) in THF (100 mL). Add trifluoroacetic anhydride (6.5 mL) in THF (100 mL) at -5°C. Allow to react for 1 hour at -5°C. After completion, concentrate the reaction mixture, add purified water, and extract with ethyl acetate. The resulting mixture is concentrated to afford the title compound (7.0 g, 84.3% yield).

[0482] (2) Preparation of N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine

[0483] Dissolve N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (7.0 g, 0.03 mol) in dichloromethane (70 mL). Add N-bromosuccinimide (7.6 g, 0.045 mol) at 0°C and allow to react for 1 hour. After completion of the reaction, concentrate and purify on a silica gel column (ethyl acetate / n-heptane = 12%) to obtain the title compound (3.5 g, yield: 38.0%).

[0484] (3) Preparation of 5-bromo-3-chloro-2-hydrazinopyrazine

[0485] Dissolve N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (3.5 g, 11 mmol) in anhydrous ethanol (60 mL), add concentrated hydrochloric acid (9 mL), and react at 100°C for 2 hours. After the reaction is complete, cool the mixture and adjust the pH to 8 with saturated sodium bicarbonate solution. Extract the mixture with ethyl acetate, wash once with water, and concentrate to obtain the title compound (2.5 g, crude product).

[0486] (4) Preparation of 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine

[0487] Dissolve 5-bromo-3-chloro-2-hydrazinopyrazine (2.5 g, crude) in triethyl orthoformate (40 mL) and react at 100°C for 2 hours. After completion, add purified water, extract with ethyl acetate, and purify with a column (ethyl acetate / n-heptane: 60%) to obtain 2.5 g of the title compound, with a two-step yield of 97.4%.

[0488] (5) Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0489] Dissolve 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, 8.6 mmol) in N-methylpyrrolidone (20 mL), add 4,4-difluoropiperidine hydrochloride (1.5 g, 9.4 mmol), and N,N-diisopropylethylamine (4.4 g, 34.4 mmol). Microwave the mixture at 100°C for 50 minutes. After completion of the reaction, cool the mixture and dropwise add purified water. A large amount of solid precipitated, which was filtered and dried to obtain 2.5 g of the desired product in a yield of 91.1%.

[0490] (6) Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate

[0491] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (2.5 g, 8 mmol) was dissolved in dioxane (30 mL), and tert-butyl carbamate (3.7 g, 32 mmol) was added. (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.3 g, 1.6 mmol) was also added. Cesium carbonate (10.4 g, 32 mmol) was then added. The mixture was reacted at 100°C under nitrogen for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and directly purified on a silica gel column (ethyl acetate:n-heptane = 65%) to obtain 1.0 g of the title compound in a yield of 35.9%.

[0492] (7) Preparation of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-amine

[0493] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate (1.2 g, 3.4 mmol) in ethyl acetate (5 mL). Add 4N HCl in ethyl acetate (6 mL) and react at 25°C for 16 hours. After completion of the reaction, concentrate to dryness and use directly in the next step (1.2 g crude product).

[0494] (8) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0495] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.1 g, 3.1 mmol) in dichloromethane (10 mL). Add N,N-dimethylformamide (0.1 mL). Add dimethyl sulfoxide (740 mg, 9.5 mmol) at 0°C and react at 25°C for 0.5 h. After completion of the reaction, concentrate to dryness and use in the next step (1.1 g crude product).

[0496] (9) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0497] 8-(4,4-Difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-amine (1.0 g, crude) was dissolved in dichloromethane (10 mL), and N,N-isopropylethylamine (1.7 g, 13.2 mmol) was added dropwise to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (1.1 g, crude) in dichloromethane (10 mL) and potassium phosphate (934 mg, 4.4 mmol). The mixture was allowed to react at 25°C for 1 hour. After completion, the reaction was quenched with water, extracted with dichloromethane, and purified on a silica gel column (ethyl acetate:n-heptane = 40%) to obtain 300 mg of the title compound, with a two-step yield of 15.0%.

[0498] (10) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0499] N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-methyl)benzamide (130 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (42 mg, 0.22 mmol), N-methylglycine (39 mg, 0.44 mmol), and potassium phosphate (187 mg, 0.88 mmol) were added and reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (82 mg, 0.66 mmol) was added and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate, purified on a concentrated silica gel column (ethyl acetate:n-heptane = 1:4), and slurried with ethyl acetate to obtain the title compound (30 mg, yield: 23.0%).

[0500] Molecular formula: C 26 H 32 F2N8O4S molecular weight: 590.65 LC-MS (M / e): 591.0 (M+H + )

[0501] 1 H-NMR(400MHz,DMSO-d6)δ:13.07(s,1H),12.32(s,1H),9.37(s,1H),8.79(s,1H),8.09(d,1H),7.30(s,1H),7.15(d,1H),4 .96(s,1H),4.45(m,4H),3.75-3.78(m,2H),3.29-3.38(m,2H),2.99(m,4H),2.51(m,4H),1.73-1.99(m,3H),0.422(m,4H).

[0502] Example 6 Preparation of N-(4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 10)

[0503] (1) Preparation of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidine

[0504] To a solution of 2,4-dichloro-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidine (2.2 g, 9.8 mmol) in acetonitrile (100 mL) were added 4,4-difluoropyridine hydrochloride (1.5 g, 9.5 mmol) and N,N-diisopropylethylamine (4.9 g, 37.9 mmol). The reaction was allowed to react at 25°C for 3 h. After completion, the system was quenched with water, and the organic phase was extracted with ethyl acetate, dried, concentrated, and spin-dried. The mixture was then purified by normal phase purification (ethyl acetate:petroleum ether = 1:3) to obtain 2.8 g of the title compound in a yield of 92.1%.

[0505] (2) Preparation of tert-butyl (4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)carbamate

[0506] To a solution of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidine (2.0 g, 6.5 mmol) in 1,4-dioxane (60 mL) were added BocNH2 (1.5 g, 12.8 mmol), RuphosPdG3 (544 mg, 0.65 mmol), and cesium carbonate (6.4 g, 19.6 mmol). The reaction was allowed to proceed at 100°C under nitrogen for 16 hours. After completion, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate, dried, concentrated, and purified by normal phase purification (ethyl acetate:petroleum ether = 1:6) to obtain 1.2 g of the title compound in a yield of 47.6%.

[0507] (3) Preparation of 4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-amine

[0508] To a solution of tert-butyl (4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)carbamate (1.2 g, 3.1 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate. The organic phase was extracted with dichloromethane, dried, concentrated, and spin-dried. The residue was then purified by normal phase purification (ethyl acetate = 100%) to obtain 800 mg of the title compound in a yield of 89.7%.

[0509] (4) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0510] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (900 mg, 2.5 mmol) in dichloromethane (20 mL) was added N,N-dimethylformamide (0.2 mL) and thionyl chloride (908 mg, 7.5 mmol) at 0°C. The reaction was continued for 30 minutes. Upon completion of the reaction, the reaction solution was concentrated to dryness and used directly in the next step.

[0511] (5) Preparation of N-(4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0512] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (N / A, 2.5 mmol) in dichloromethane (15 mL) was added potassium phosphate (531 mg, 2.5 mmol), followed by 4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-amine (363 mg, 1.3 mmol) and N,N-diisopropylethylamine (1.9 g, 14.7 mmol) in dichloromethane (10 mL) at 0°C. The reaction was continued at 25°C for 16 hours. After completion of the reaction, water was added, and the organic phase was extracted with dichloromethane, dried, concentrated, and spin-dried. The product was then purified by normal phase purification (ethyl acetate:petroleum ether = 3:7) to afford 100 mg of the title compound, with a two-step yield of 6.3%.

[0513] (6) Preparation of N-(4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopentyl[d]pyrimidin-2-yl)-4-(2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0514] N-(4-(4,4-difluoropiperidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (25 mg, 0.13 mmol), N-methylglycine (23 mg, 0.26 mmol), potassium phosphate (138 mg, 0.65 mmol), and 2-hydroxyethane-1-sulfonamide (49 mg, 0.391 mmol) were added. The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, concentrated, and purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain 6 mg of the title compound in a 7.5% yield.

[0515] Molecular formula: C28 H 34 F4N6O4S molecular weight: 626.7 LC-MS (M / e): 627.2 (M+H + )

[0516] 1 H-NMR(400MHz, DMSO-d6)δ:12.80-12.70(m,1H),10.30-10.05(m,1H),7.94(d,J=8.4Hz,1H),7.21(s,1H),7.09(d,J=8.4Hz,1H),5.10-4.90( m,1H),3.95-3.75(m,6H),3.25-3.15(m,2H),3.05-2.90(m,4H),2.60- 2.50(m,2H),2.20-2.00(m,4H),1.80-1.50(m,6H),0.90-0.70(m,4H).

[0517] Example 7 Preparation of N-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide (Compound 11)

[0518] (1) Preparation of 6-chloro-8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazine

[0519] Dissolve 6,8-dichloroimidazo[1,2-a]pyrazine (3 g, 16 mmol), 3,3-difluoroazetidine hydrochloride (2.2 g, 17 mmol), and DIPEA (6.2 g, 48 mmol) in NMP (30 mL) and react at 100°C for 1 h. After completion of the reaction, cool to room temperature, pour the reaction mixture into water, filter, and dry the filter cake to obtain the title compound (3 g, yield: 76.7%).

[0520] (2) Preparation of tert-butyl (8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamate

[0521] 6-Chloro-8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazine (1.3 g, 5.3 mmol), BocNH2 (1.9 g, 15.9 mmol), RuphosPdG3 (444 mg, 0.53 mmol), and cesium carbonate (6.9 g, 21.2 mmol) were dissolved in 1,4-dioxane (50 mL) and reacted at 100°C under nitrogen for 8 hours. After completion of the reaction, the mixture was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (1.1 g, yield: 63.8%).

[0522] (3) Preparation of 8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-amine

[0523] Dissolve tert-butyl (8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamate (1.1 g, 3.4 mmol) in DCM (10 mL), add TFA (4 mL), and react at 30°C for 3 hours. After completion of the reaction, remove the solvent under reduced pressure, adjust the pH to 8-9 with saturated sodium bicarbonate solution, extract with DCM, and spin dry the organic phase to obtain 680 mg of the product (88.5% yield).

[0524] (4) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid

[0525] 2-Fluoro-4-iodobenzoic acid (6 g, 22.6 mmol) was dissolved in DMSO (50 mL). TFA, 6-azaspiro[2.5]octane hydrochloride (4.3 g, 29.4 mmol), and potassium carbonate (9.4 g, 67.8 mmol) were added and reacted at 140°C for 16 h. After completion of the reaction, the reaction solution was poured into water and extracted with n-hexane. The aqueous phase was adjusted to a pH of 5-6 with 2M dilute hydrochloric acid, filtered, and the filter cake dried to obtain 5 g of the product in a yield of 62.0%.

[0526] (5) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0527] DMF (0.1 mL) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.1 g, 3 mmol) and thionyl chloride (1.1 g, 9 mmol) in dichloromethane (10 mL) at 0°C. The reaction was continued for 1 hour. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0528] (6) Preparation of N-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0529] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude product from the previous step) in dichloromethane (10 mL) was added dropwise potassium phosphate (510 mg, 2.4 mmol) at 0°C. Then, 8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-amine (550 mg, 2.4 mmol) and DIPEA (929 mg, 7.2 mmol) in dichloromethane (10 mL) were added dropwise. The reaction was continued at 25°C for 1 hour. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (650 mg, yield: 47.9%).

[0530] (7) Preparation of N-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-methyl)benzamide

[0531] N-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octane-6-methyl)benzamide (150 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (51 mg, 0.27 mmol), N-methylglycine (48 mg, 0.54 mmol), and potassium phosphate (229 mg, 1.08 mmol) were added. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (101 mg, 0.81 mmol) was then added and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, and purified on a silica gel column (ethyl acetate:petroleum ether = 4:1) to obtain the title compound (75 mg, yield: 49.4%).

[0532] Molecular formula: C 25 H 29 F2N7O4S molecular weight: 561.6 LC-MS (M / e): 562.1 (M+H + )

[0533] 1H-NMR(400MHz,DMSO-d6)δ:13.18(s,1H),10.19(s,1H),8.82(s,1H),8.07-8.10(m,2H),7.58(s,1H),7.30(s,1H),7.14-7.1 7(m,1H),4.93(s,1H),4.76-4.82(m,4H),3.72-3.80(m,2H),3.36-3.38(m,4H),2.99(s,4H),1.70-1.90(m,2H),0.42(s,4H).

[0534] Example 8 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (Compound 12)

[0535] (1) Preparation of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate

[0536] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.17 mmol) was dissolved in DMSO (8 mL), and potassium metabisulfite (57 mg, 0.26 mmol), sodium formate (25 mg, 0.37 mmol), triphenylphosphine (7 mg, 0.026 mmol), 1,10-phenanthroline (5 mg, The product was reacted with tetrabutylammonium bromide (84 mg, 0.26 mmol) and palladium acetate (1 mg, 0.0044 mmol) at 70°C under nitrogen protection for 45 minutes. The temperature was then lowered and ethyl bromoacetate (43 mg, 0.26 mmol) was added and the reaction was continued for 30 minutes. After completion of the reaction, the product was quenched with water, extracted with ethyl acetate, and concentrated. The residue was purified on a silica gel column (ethyl acetate: petroleum ether = 1:4) to obtain the title compound (40 mg, yield: 38.4%).

[0537] (2) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0538] Lithium borohydride (2 mg, 0.092 mmol) was added to a solution of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (40 mg, 0.065 mmol) in tetrahydrofuran (10 mL) at 0°C and allowed to react for 3 hours. After completion of the reaction, the product was quenched with water, extracted with ethyl acetate, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford the title compound (5 mg, yield: 13.4%).

[0539] Molecular formula: C 27 H 32 F2N6O4S molecular weight: 574.65 LC-MS (M / e): 575.0 (M+H + )

[0540] 1 H-NMR(400MHz, CDCl3-d6)δ:12.71(s,1H),8.84(s,1H),8.50(m,1H),7.92(m,1H),7.86(m,1H),7.52(m,2H),4.50 (m,4H),4.10(m,2H),3.41(m,2H),3.18(m,4H),2.64(m,1H),2.23(m,4H),1.85(m,2H),1.28(m,2H),0.52(m,4H).

[0541] Example 9 Preparation of 4-(cyclopropylsulfonyl)-N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 13)

[0542] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.17 mmol), sodium cyclopropanesulfinate (44 mg, 0.34 mmol), potassium carbonate (5 mg, 0.034 mmol), cuprous iodide (3 mg, 0.016 mmol), and L-proline (4 mg, 0.034 mmol) were added to a DMSO (4 ml) solution. After nitrogen replacement, the mixture was microwaved at 140°C for 1 hour. After completion, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (45 mg, yield: 46.4%).

[0543] Molecular formula: C28 H 32 F2N6O3S molecular weight: 570.66 LC-MS (M / e): 571.0 (M+H + )

[0544] 1 H-NMR(400MHz, CDCl3-d6)δ:12.76(s,1H),8.87(s,1H),8.32-8.30(m,1H),8.12(s,1H),7.91(m,1H),7.84-7.82(m, 1H),7.58(s,1H),4.44(m,4H),3.10(m,4H),3.01(m,1H),2.16-2.09(m,4H),1.74(m,4H),1.12(m,4H),1.08(m,4H).

[0545] Example 10 Preparation of (4-(2-hydroxyethyl)sulfonyl)-N-(8-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 15)

[0546] (1) Preparation of 4-(6-chloroimidazo[1,2-a]pyrazin-8-yl)morpholine

[0547] Dissolve 6,8-dichloroimidazo[1,2-a]pyrazine (3 g, 16 mmol) and morpholine (1.4 g, 16 mmol) in NMP (20 mL) and react at 100°C for 3 h. After completion, cool to room temperature, pour the reaction mixture into water, filter, and dry the filter cake to obtain the title compound (3 g, yield: 78.5%).

[0548] (2) Preparation of tert-butyl (8-morpholinoyl imidazo[1,2-a]pyrazin-6-yl)carbamate

[0549] 4-(6-chloroimidazo[1,2-a]pyrazin-8-yl)morpholine (1.2 g, 5 mmol), BocNH2 (1.8 g, 15 mmol), RuphosPdG3 (419 mg, 0.5 mmol), and cesium carbonate (6.5 g, 20 mmol) were dissolved in 1,4-dioxane (50 mL) and reacted at 100°C under nitrogen for 8 hours. After completion of the reaction, the mixture was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (1.2 g, yield: 75.0%).

[0550] (3) Preparation of 8-morpholinoimidazolo[1,2-a]pyrazin-6-amine

[0551] Dissolve tert-butyl (8-morpholinoimidazolo[1,2-a]pyrazin-6-yl)carbamate (1.2 g, 3.75 mmol) in DCM (8 mL), add TFA (4 mL), and react at 30°C for 3 hours. After completion of the reaction, remove the solvent under reduced pressure, adjust the pH to 8-9 with saturated sodium bicarbonate solution, extract with DCM, and spin dry the organic phase to obtain 800 mg of the product in a 97.0% yield.

[0552] (4) Preparation of 4-iodo-N-(8-morpholinoimidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0553] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (706 mg, 1.88 mmol) in dichloromethane (10 mL) at 0°C was added potassium phosphate (399 mg, 1.88 mmol) dropwise. Then, 8-morpholinoimidazolo[1,2-a]pyrazin-6-amine (414 mg, 1.88 mmol) and DIPEA (728 mg, 5.64 mmol) in dichloromethane (10 mL) were added dropwise. The reaction was continued at 25°C for 1 hour. After completion, the reaction was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (500 mg, yield: 47.6%).

[0554] (5) Preparation of 4-(2-hydroxyethyl)sulfonyl)-N-(8-morpholinoimidazolo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0555] 4-Iodo-N-(8-morpholinoylimidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (68 mg, 0.36 mmol), N-methylglycine (64 mg, 0.72 mmol), and potassium phosphate (306 mg, 1.44 mmol) were added. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (135 mg, 1.08 mmol) was added, and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride, filtered, and the filter cake was slurried with methanol to obtain the title compound (9.7 mg, yield: 4.8%).

[0556] Molecular formula: C 26 H 33 N7O5S molecular weight: 555.7 LC-MS (M / e): 556.2 (M+H + )

[0557] 1 H-NMR(400MHz,DMSO-d6)δ:12.97(s,1H),10.19(s,1H),8.80(s,1H),8.05-8.10(m,2H),7.54(s,1H),7.28(s,1H), 7.06-7.12(m,1H),4.28(s,4H),3.72-3.80(m,6H),3.35-3.45(m,4H),2.99(s,4H),1.70-1.90(m,2H),0.42(s,4H).

[0558] Example 11 Preparation of (R)-4-((2-hydroxyethyl)sulfonamide)-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 16)

[0559] 1. Preparation of 6,8-dichloroimidazo[1,2-a]pyrazine

[0560] Chloroacetaldehyde (40% aqueous solution) (23.2 g, 0.118 mol) was added to 3,5-dichloropyrazin-2-amine (9.64 g, 0.059 mol) in acetonitrile (150 mL) and reacted at 75°C for 3 hours. After completion of the reaction, the temperature was lowered to 20°C, whereupon a solid precipitated. Filtering afforded the title compound (9.5 g, 85.6% yield).

[0561] 2. Preparation of (R)-4-(6-chloroimidazo[1,2-a]pyrazin-8-yl)-2-methylmorpholine

[0562] 6,8-Dichloroimidazo[1,2-a]pyrazine (5.8 g, 31 mmol), (R)-2-methylmorpholine hydrochloride (4.7 g, 34 mmol), DIPEA (12.0 g, 93 mmol), and NMP (50 mL) were added to a reaction flask and reacted at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and poured into 500 mL of water. The precipitated solid was filtered to obtain 8.0 g of the product.

[0563] 3. Preparation of tert-butyl (R)-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)carbamate

[0564] (R)-4-(6-chloroimidazo[1,2-a]pyrazin-8-yl)-2-methylmorpholine (7.7 g, 30 mmol), BocNH2 (7.0 g, 60 mmol), RuphosPdG3 (2.5 g, 3 mmol), and cesium carbonate (19.5 g, 60 mmol) were added sequentially to 1,4-dioxane (100 mL). The mixture was reacted at 100°C under nitrogen for 8 hours. After completion of the reaction, the mixture was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (3.6 g, yield: 36%).

[0565] 4. Preparation of (R)-8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-amine

[0566] Trifluoroacetic acid (10 mL) was added to tert-butyl (R)-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)carbamate (1.6 g, 4.8 mmol) in DCM (20 mL) at 25°C and allowed to react for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure to yield 1.5 g of the product.

[0567] 5. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0568] DMF (0.1 mL) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.0 g, 5.6 mmol) and oxalyl chloride (1.1 g, 8.4 mmol) in dichloromethane (40 mL) at 0°C. The reaction was continued for 1 hour. Upon completion, the reaction mixture was used directly in the next step.

[0569] 6. Preparation of (R)-4-iodo-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0570] A solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride in dichloromethane (40 mL) was added dropwise to (R)-8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-amine (1.4 g, 6 mmol) and DIPEA (2.0 g, 15.5 mmol) in dichloromethane (20 mL) at 0°C. The reaction was continued for 1 hour. After completion, the reaction was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:5) to obtain the title compound (1.5 g, two-step yield: 46.8%).

[0571] 7. Preparation of (R)-4-((2-hydroxyethyl)sulfonamide)-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0572] (R)-4-iodo-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.35 mmol) was dissolved in N,N-dimethylacetamide (5 mL). Cuprous iodide (67 mg, 0.35 mmol), N-methylglycine (31 mg, 0.35 mmol), and potassium phosphate (372 mg, 1.75 mmol) were added. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (88 mg, 0.70 mmol) was then added and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (90 mg, yield: 45.1%).

[0573] Molecular formula: C 27 H 35 N7O5S molecular weight: 569.7 LC-MS (M / e): 570.7 (M+H + )

[0574] 1 H-NMR(400MHz,DMSO-d6)δ:12.75(s,1H),10.18(s,1H),8.81(s,1H),8.08(m,2H),7.55(m,1H), 7.28(m,1H),7.13(m,1H),5.32(m,2H),4.95(m,1H),3.97(m,1H),3.76(m,3H),3.68(m,2H),3. 33(m,2H),2.99(m,4H),2.87(m,1H),1.99(m,1H),1.75(m,3H),1.18-1.24(m,3H),0.41(m,4H).

[0575] Example 12 Preparation of (R)-4-iodo-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 17)

[0576] (R)-4-iodo-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl) (150 mg, 0.26 mmol), sodium cyclopropanesulfinate (67 mg, 0.52 mmol), potassium carbonate (7 mg, 0.052 mmol), cuprous iodide (10 mg, 0.052 mmol), and L-proline (6 mg, 0.052 mmol) were added to a DMSO (4 ml) solution. After nitrogen replacement, the solution was microwaved at 140°C for 1 hour. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain 58 mg of the title compound in a yield of 40.5%.

[0577] Molecular formula: C 28 H 34 N6O4S molecular weight: 550.68 LC-MS (M / e): 551.0 (M+H + )

[0578] 1 H-NMR(400MHz,DMSO-d6)δ:12.64(s,1H),8.84(s,1H),8.32-8.30(m,1H),8.11(s,1H),7.90(m,1H),7.83-7.81(m,1H),7.57(s,1H),5.32-5. 35(m,2H),3.97(m,1H),3.65(m,2H),3.20(m,1H),3.12(m,4H),3.02(m ,1H),2.98(m,1H),1.74(m,4H),1.23(m,5H),1.10(m,2H),0.42(m,4H).

[0579] Example 13 Preparation of (R)-4-((2-hydroxyethyl)sulfonyl)-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 18)

[0580] 1. Preparation of ethyl (R)-2-((4-((8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate

[0581] (R)-4-iodo-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.35 mmol) was dissolved in DMSO (10 mL), and potassium metabisulfite (118 mg, 0.53 mmol), sodium formate (53 mg, 0.77 mmol), triphenylphosphine (14 mg, 0.053 mmol), 1,10-phenanthroline ( The product was reacted with tetrabutylammonium bromide (10 mg, 0.053 mmol), tetrabutylammonium bromide (171 mg, 0.53 mmol) and palladium acetate (2.6 mg, 0.02 mmol) at 70°C under nitrogen for 45 minutes. The temperature was then lowered and ethyl bromoacetate (89 mg, 0.53 mmol) was added and the reaction was continued for 10 minutes. After completion of the reaction, the product was quenched with water and extracted with ethyl acetate. The product was concentrated and purified on a silica gel column (ethyl acetate: petroleum ether = 1:4) to obtain the title compound (100 mg, yield: 47.9%).

[0582] 2. Preparation of (R)-4-((2-hydroxyethyl)sulfonyl)-N-(8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0583] Lithium borohydride (7 mg, 0.3 mmol) was added to a solution of (R)-ethyl 2-((4-((8-(2-methylmorpholino)imidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (90 mg, 0.15 mmol) in tetrahydrofuran (20 mL) at 25°C and allowed to react for 30 minutes. After completion of the reaction, the product was quenched with water, extracted with ethyl acetate, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford the title compound (35 mg, 42.1% yield).

[0584] Molecular formula: C 27 H 34 N6O5S molecular weight: 554.7 LC-MS (M / e): 555.7 (M+H + )

[0585] 1H-NMR(400MHz,DMSO-d6)δ:12.70(s,1H),8.83(s,1H),8.30(s,1H),8.11(m,1H),7.93(m,1H),7.83(m,1H),7.81(m,1H),7.56(m,1H),5.76(m,2 H),4.95(m,1H),3.98(m,1H),3.75(m,2H),3.71(m,2H)3.68(m,2H),3.1 0(m,4H),2.87(m,1H),1.99-1.75(m,4H),1.18-1.34(m,3H)0.40(m,4H).

[0586] Example 14 Preparation of (R)-N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-6-((1-hydroxypropyl-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 19)

[0587] (1) Preparation of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid

[0588] 2,6-Difluoronicotinic acid (5.0 g, 31.4 mmol), 6-azaspiro[2.5]octane hydrochloride (5.1 g, 34.6 mmol), and DIPEA (12.2 g, 94.5 mmol) in 1,4-dioxane (50 mL) were reacted at 30°C for 15 hours. After completion, the reaction solution was poured into water to precipitate a solid, which was then dried to afford the desired product (6.0 g, 76.4% yield).

[0589] (2) Preparation of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride

[0590] DMF (0.1 mL) was added to 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (800 mg, 3.2 mmol) and oxalyl chloride (812 mg, 6.4 mmol) in dichloromethane (10 mL) at 30°C and the reaction was continued for 1 hour. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0591] (3) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0592] At 0°C, a solution of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride (crude product from the previous step) in dichloromethane (5 mL) was added dropwise to 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-amine (500 mg, 2.0 mmol) and DIPEA (775 mg, 6.0 mmol) in dichloromethane (15 mL). The reaction was continued for 1 hour. After completion of the reaction, the sample was directly added to silica gel and purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (140 mg, yield: 14.6%).

[0593] (4) Preparation of (R)-N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-6-((1-hydroxypropyl-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0594] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (140 mg, 0.29 mmol) was dissolved in DMSO (10 mL), and DIPEA (112 mg, 0.87 mmol) and D-aminopropanol (44 mg, 0.58 mmol) were added. The mixture was allowed to react at 25°C for 15 h. After completion, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The residue was purified on a silica gel plate (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (60 mg, yield: 38.5%).

[0595] Molecular formula: C 27 H 34 F2N8O2 molecular weight: 540.6 LC-MS (M / e): 541.1 (M+H + )

[0596] 1 H-NMR(400MHz,DMSO-d6)δ:12.30(s,1H),8.77(s,1H),8.07(s,1H),7.99(m,1H),7.54(s,1H),7.04(m,1H),6.39(m,1H) ,4.74(m,1H),4.43(m,4H),4.03(m,1H),3.50(m,2H),3.09(m,4H),2.15(m,4H),1.71(m,4H),1.27(m,3H),0.48(m,4H).

[0597] Example 15 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (Compound 20)

[0598] (1) Preparation of 6,8-dichloroimidazo[1,2-a]pyrazine

[0599] Chloroacetaldehyde (14.4 g, 73.4 mmol, 40% aqueous solution) was added to 3,5-dichloropyrazin-2-amine (6.0 g, 36.6 mmol) in DMF (50 mL) and allowed to react at 100°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and poured into water. Extraction was performed three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the ethyl acetate was removed under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (5.5 g, yield: 80.0%).

[0600] (2) Preparation of 6,8-dichloro-3-fluoroimidazo[1,2-a]pyrazine

[0601] Select F (10.0 g, 28.2 mmol) was added to 6,8-dichloroimidazo[1,2-a]pyrazine (5.5 g, 29.3 mmol) in acetonitrile (50 mL) and allowed to react at 30°C for 2 hours. Upon completion, the reaction solution was directly spin-dried, and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (2.1 g, yield: 34.8%).

[0602] (3) Preparation of 6-chloro-8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazine

[0603] 6,8-Dichloro-3-fluoroimidazo[1,2-a]pyrazine (2.1 g, 10.2 mmol), 4,4-difluoropiperidine hydrochloride (1.4 g, 8.9 mmol), DIPEA (4.0 g, 31.0 mmol), and NMP (8 mL) were added to a microwave oven and reacted at 100°C for 50 minutes. After completion of the reaction, the mixture was cooled to room temperature and poured into water. Extraction was performed three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the ethyl acetate was removed under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:2) to obtain the title compound (2.7 g, yield: 91.1%).

[0604] (4) Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)carbamate

[0605] A mixture of 6-chloro-8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazine (2.7 g, 9.3 mmol), BocNH2 (2.2 g, 18.8 mmol), RuphosPdG3 (1.6 g, 1.9 mmol), and cesium carbonate (6.0 g, 18.4 mmol) in 1,4-dioxane (40 mL) was reacted at 100°C under nitrogen for 8 hours. After completion, the product was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (2.4 g, yield: 69.6%).

[0606] (5) Preparation of 8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-amine

[0607] Trifluoroacetic acid (4 mL) was added to tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)carbamate (200 mg, 0.54 mmol) in dichloromethane (2 mL) at 30°C for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was slurried with methyl tert-butyl ether to obtain the desired product (80 g, yield: 54.8%).

[0608] (6) Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0609] DMF (0.1 mL) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 0.56 mmol) and oxalyl chloride (140 mg, 1.1 mmol) in dichloromethane (40 mL) at 30°C and the reaction was continued for 1 hour. Upon completion, the reaction solution was concentrated to dryness and used directly in the next step.

[0610] (7) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0611] At 0°C, a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude product from the previous step) in dichloromethane (5 mL) was added dropwise to 8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-amine (80 mg, 0.29 mmol) and DIPEA (112 mg, 0.87 mmol) in dichloromethane (10 mL). The reaction was continued for 3 hours. After completion, the product was purified directly on a silica gel plate (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (30 mg, yield: 16.7%).

[0612] (8) Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0613] N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30 mg, 0.049 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (10 mg, 0.052 mmol), N-methylglycine (5 mg, 0.056 mmol), and potassium phosphate (51 mg, 0.24 mmol) were added. The mixture was reacted at 50°C for 5 minutes. 2-Hydroxyethane-1-sulfonamide (12 mg, 0.096 mmol) was then added. The mixture was reacted at 100°C under nitrogen for 2 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel plate (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (11 mg, yield: 36.8%).

[0614] Molecular formula: C 27 H 32 F3N7O4S molecular weight: 607.7 LC-MS (M / e): 608.1 (M+H + )

[0615] 1 H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),10.15(brs,1H),8.44(s,1H),8.08(m,1H),7.40(m,1H),7.30(m,1H),7.16(m ,1H),4.98(brs,1H),4.42(m,4H),3.77(m,2H),3.33(m,2H),3.04(m,4H),2.11(m,4H),1.98-1.67(m,4H),0.42(m,4H).

[0616] Example 16 Preparation of (R)-N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-6-((1-hydroxypropyl-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Compound 21)

[0617] 1. Preparation of N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine

[0618] Dissolve 2-chloro-3-hydrazinopyrazine (10.0 g, 69 mmol) in THF (100 mL). Add trifluoroacetic anhydride (12 mL) in THF (100 mL) at -5°C. Allow to react at -5°C for 1 hour. After completion of the reaction, concentrate the reaction mixture, add purified water, and extract with ethyl acetate. The resulting mixture is concentrated to afford the title compound (12.0 g, yield: 71.9%).

[0619] 2. Preparation of N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine

[0620] Dissolve N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (12.0 g, 0.05 mol) in dichloromethane (150 mL). Add N-bromosuccinimide (13.3 g, 0.07 mol) at 0°C and allow to react for 1 hour. After completion of the reaction, concentrate and purify on a silica gel column (ethyl acetate / n-heptane = 15%) to obtain the title compound (12.0 g, yield: 75.5%).

[0621] 3. Preparation of 5-bromo-3-chloro-2-hydrazinopyrazine

[0622] Dissolve N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetylhydrazine (12.0 g, 0.04 mol) in anhydrous ethanol (150 mL), add concentrated hydrochloric acid (12 mL), and react at 100°C for 2 hours. After completion of the reaction, cool the mixture and adjust the pH to 8 with saturated sodium bicarbonate solution. Extract the mixture with ethyl acetate, wash once with water, and concentrate to obtain the title compound (8.0 g, yield: 95.2%).

[0623] 4. Preparation of 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine

[0624] Dissolve 5-bromo-3-chloro-2-hydrazinopyrazine (8.0 g, 35.9 mmol) in triethyl orthoformate (120 mL) and react at 100°C for 2 hours. After completion, add purified water, extract with ethyl acetate, and concentrate. The residue is purified by column chromatography (ethyl acetate / n-heptane: 60%) to obtain 6.5 g of the title compound in a yield of 77.8%.

[0625] 5. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0626] Dissolve 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (6.5 g, 27.8 mmol) in N-methylpyrrolidone (30 mL), add 4,4-difluoropiperidine hydrochloride (4.8 g, 30.7 mmol), and N,N-diisopropylethylamine (14.4 g, 111.6 mmol). Microwave the mixture at 100°C for 50 minutes. After completion of the reaction, cool the mixture and dropwise add purified water. A large amount of solid precipitated, which was filtered and dried to obtain 8.0 g of the desired product in a 90.4% yield.

[0627] 6. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate

[0628] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (8.0 g, 25 mol) was dissolved in dioxane (80 mL), and tert-butyl aminomethoxy ester (11.8 g, 100 mmol) was added. (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (2.1 g, 2.5 mmol) was also added. Cesium carbonate (32.6 g, 100 mmol) was then added and the mixture was reacted at 100°C under nitrogen for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and directly purified on a silica gel column (ethyl acetate:n-heptane = 55%) to obtain 8.0 g of the title compound in an 89.4% yield.

[0629] 7. Preparation of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-amine

[0630] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate (4.0 g, 11.3 mmol) in ethyl acetate (10 mL). Add 4N HCl in ethyl acetate (20 mL) and allow to react at 25°C for 16 hours. After completion of the reaction, concentrate the product and use it directly in the next step (3.0 g crude product).

[0631] 8. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0632] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.5 g, 7 mmol) in dichloromethane (20 mL), add N,N-dimethylformamide (0.1 mL), and then add dimethyl sulfoxide (1.8 g, 23 mmol) at 0°C. React at 25°C for 0.5 h. After completion of the reaction, concentrate the mixture and use it in the next step (3.0 g crude product).

[0633] 9. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0634] 8-(4,4-Difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-amine (3.0 g, crude) was dissolved in dichloromethane (15 mL), and N,N-isopropylethylamine (4.5 g, 35.1 mmol) was added dropwise to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (3.0 g, crude) in dichloromethane (15 mL) and potassium phosphate (2.5 g, 11.7 mmol). The mixture was allowed to react at 25°C for 1 hour. After completion, the reaction was quenched with water, extracted with dichloromethane, and concentrated. The residue was purified on a silica gel column (ethyl acetate:n-heptane = 60%) to obtain 400 mg of the title compound, with a two-step yield of 9.6%.

[0635] 10. Preparation of (R)-N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-6-((1-hydroxypropyl-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0636] N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL). D-aminopropanol (43 mg, 0.58 mmol) and N,N-diisopropylethylamine (112 mg, 0.87 mmol) were added and reacted at 80°C for 3 h. After completion, the reaction was concentrated, and the residue was purified on a silica gel column (ethyl acetate:n-heptane = 80%) and slurried in ethyl acetate to obtain the title compound (28 mg, yield: 21.9%).

[0637] Molecular formula: C 26 H 33 F2N9O2 molecular weight: 541.6 LC-MS (M / e): 541.3 (M+H + )

[0638] 1H-NMR(400MHz,DMSO-d6)δ:12.50(s,1H),9.35(s,1H),8.72(s,1H),8.00 -8.98(m,1H),7.12-7.10(m,1H),6.40-6.39(m,1H),4.75-4.72(m,1H),4. 44(m,4H),4.06-4.02(m,1H),3.52-3.48(m,1H),3.41-3.33(m,1H),3.08 -3.06(m,4H),2.51-2.12(m,4H),1.69(m,4H),1.24(m,3H),0.422(m,4H).

[0639] Example 17 Preparation of 4-(cyclopropylsulfonyl)-N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 23)

[0640] N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.13 mmol), sodium cyclopropanesulfinate (33 mg, 0.26 mmol), potassium carbonate (4 mg, 0.029 mmol), cuprous iodide (5 mg, 0.026 mmol), and L-proline (3 mg, 0.026 mmol) were added to a DMSO (4 ml) solution. After nitrogen replacement, the mixture was microwaved at 140°C for 1 hour. After completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (20 mg).

[0641] Molecular formula: C 28 H 31 F3N6O3S molecular weight: 588.65 LC-MS (M / e): 589.0 (M+H + )

[0642] 1 H-NMR(400MHz,DMSO-d6)δ:12.93(s,1H),8.45(s,1H),8.32-8.30(m,1H),7.93(s,1H),7.84-7.82(m,1H),7. 43-7.41(m,1H),4.42(m,4H),3.12(m,4H),3.03(m,1H),2.13(m,4H),1.72(m,4H),1.20(m,4H),0.44(m,4H).

[0643] Example 18 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 24)

[0644] 1. Preparation of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine

[0645] To a solution of 3,5-dibromopyrazin-2-amine (5.0 g, 19.8 mmol) in isopropanol (50 mL) was added 1-bromo-2,2-dimethoxypropane (5.4 g, 29.5 mmol) and pyridine p-toluenesulfonate (498 mg, 2.0 mmol). The mixture was allowed to react at 70°C for 16 hours. After completion, the mixture was cooled to room temperature, the pH was adjusted to alkaline with triethylamine, and the mixture was dried by rotary evaporation. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:2) to obtain the title compound (2.1 g, yield: 36.5%).

[0646] Preparation of 2,6,8-dibromo-3-fluoro-2-methylimidazo[1,2-a]pyrazine

[0647] To a solution of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine (2.1 g, 7.2 mmol) in acetonitrile (30 mL) was added N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (3.8 g, 10.7 mmol) and the mixture was allowed to react at 25°C for 16 h. After completion, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate and concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:9) to afford the title compound (560 mg, yield: 25.1%).

[0648] 3. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazine

[0649] To a solution of 6,8-dibromo-3-fluoro-2-methylimidazo[1,2-a]pyrazine (560 mg, 1.8 mmol) in N-methylpyrrolidone (10 mL) were added 4,4-difluoropiperidine (369 mg, 2.3 mmol) and N,N-diisopropylethylamine (698 mg, 5.4 mmol). The mixture was allowed to react at 100°C for 1 h. After completion, the reaction was quenched with water, the organic phase was extracted with ethyl acetate, and the concentrated residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:10) to afford the title compound (530 mg, yield: 83.7%).

[0650] 4. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamate

[0651] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazine (530 mg, 1.5 mmol) in 1,4-dioxane (20 mL), tert-butyl carbamate (352 mg, 3.0 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (126 mg, 0.15 mmol), and cesium carbonate (1.5 g, 4.6 mmol) were reacted at 100°C for 3 hours under nitrogen. The reaction was quenched with water, and the organic phase was extracted with ethyl acetate, dried, and concentrated. The residue was purified on a silica gel column (dichloromethane:petroleum ether = 1:9) to obtain the title compound (300 mg, yield: 51.3%).

[0652] 5. Preparation of 8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-amine trifluoroacetate

[0653] To a solution of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamate (250 mg, 0.65 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) and the mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the crude product was used directly in the next step.

[0654] 6. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0655] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (232 mg, 0.65 mmol) in dichloromethane (10 mL) was added N,N-dimethylformamide (0.1 mL) at 25°C. Thionyl chloride (236 mg, 2.0 mmol) was then added at 0°C and the reaction continued for 30 minutes. After completion of the reaction, the reaction solution was concentrated to dryness and used directly in the next step.

[0656] 7. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0657] To a solution of 8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-amine trifluoroacetate (crude, 0.65 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (840 mg, 6.5 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude, 0.65 mmol) at -10°C. The reaction was continued for 10 minutes. After completion, the system was quenched with water, the organic phase was extracted with dichloromethane, and concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:8) to obtain the title compound (250 mg, two-step yield: 61.7%).

[0658] 8. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0659] To a solution of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (170 mg, 0.27 mmol) in N,N-dimethylformamide (10 mL) were added cuprous iodide (51 mg, 0.27 mmol), N-methylglycine (48 mg, 0.54 mmol), potassium phosphate (287 mg, 1.4 mmol), and 2-hydroxyethane-1-sulfonamide (101 mg, 0.81 mmol). The mixture was reacted at 100°C under nitrogen for 3 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 2:1) to obtain the title compound (35 mg, yield: 20.7%).

[0660] Molecular formula: C 28 H 34 F3N7O4S molecular weight: 621.7 LC-MS (M / e): 622.2 (M+H + )

[0661] 1H-NMR(400MHz,DMSO-d6)δ:13.03(s,1H),10.22(s,1H),8.40(s,1H),8.09-8.07(m,1H),7.29-7.28(m,1H),7.16-7.13(m,1H),4.95(s,1H),4.4 5-4.35(m,4H),3.80-3.70(m,2H),3.40-3.30(m,2H),3.10-2.92(m,4H) ,2.32(s,3H),2.22-2.10(m,4H),1.90-1.60(m,4H),0.42-0.40(m,4H).

[0662] Example 19 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 25)

[0663] 1. Preparation of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate

[0664] N-(8-(4,4-difluoropiperidin-1-yl)-3-imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.24 mmol) was dissolved in DMSO (6 mL), and potassium metabisulfite (80 mg, 0.36 mmol), sodium formate (36 mg, 0.53 mmol), triphenylphosphine (9 mg, 0.036 mmol), 1,10-phenanthroline were added. (6 mg, 0.036 mmol), tetrabutylammonium bromide (116 mg, 0.36 mmol) and palladium acetate (3 mg, 0.012 mmol) were reacted at 70°C under nitrogen protection for 45 minutes. The temperature was then lowered and ethyl bromoacetate (60 mg, 0.36 mmol) was added and the reaction was continued for 30 minutes. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was concentrated and purified on a silica gel column (ethyl acetate: petroleum ether = 1:1) to give the title compound (50 mg, yield 32.8%).

[0665] 2. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide

[0666] Lithium borohydride (4 mg, 0.19 mmol) was added to a solution of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (50 mg, 0.08 mmol) in tetrahydrofuran (5 ml) at 0°C and allowed to react for 3 hours. After completion of the reaction, methanol was added for quenching. The product was concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 3:2) to afford the title compound (2.0 mg, yield: 12.7%).

[0667] Molecular formula: C 27 H 31 F3N6O4S molecular weight: 592.64 LC-MS (M / e): 593.0 (M+H + )

[0668] 1 H-NMR(400MHz, DMSO-d6)δ:12.98(s,1H),8.45(s,1H),8.31~8.29(m,1H),7.95(m,1H),7.84~7.82(m,1H),7.63~7.60(m, 1H),4.95(m,1H),4.26(m,4H),3.76~3.72(m,2H),3.59~3.57(m,2H),3.11(m,4H),2.13(m,4H),1.72(m,4H),0.42(m,4H).

[0669] Example 20 Preparation of 4-(cyclopropylsulfonyl)-N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 26)

[0670] To a solution of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide (40 mg, 0.064 mmol) in dimethyl sulfoxide (2 mL) were added cuprous iodide (12 mg, 0.063 mmol), L-proline (15 mg, 0.13 mmol), potassium carbonate (18 mg, 0.13 mmol), and sodium cyclopropylsulfinate (25 mg, 0.20 mmol). The mixture was reacted in a microwave oven at 140°C under nitrogen protection for 1 hour. After completion, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (35 mg, yield: 90.7%).

[0671] Molecular formula: C 29 H 33 F3N6O3S molecular weight: 602.7 LC-MS (M / e): 603.2 (M+H + )

[0672] 1 H-NMR (400MHz, CDCl3) δ: 12.80 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 8.4Hz, 1H), 7.89 (s, 1H), 7.82-7.80 (m, 1H), 4.47-4.44 (m, 4H), 3.20-3.1 5(m,4H),2.55-2.49(m,1H),2.39(s,3H),2.20-2.12(m,4H),2.10-1.75(m,4H),1.45-1.35(m,2H),1.20-1.10(m,2H),0.51-0.49(m,4H).

[0673] Example 21 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide (Compound 27)

[0674] 1. Preparation of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-ylphenyl)sulfonyl)acetate

[0675] N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide (40 mg, 0.064 mmol) was dissolved in dimethyl sulfoxide (5 mL), and potassium metabisulfite (21 mg, 0.094 mmol), sodium formate (10 mg, 0.15 mmol), triphenylphosphine (3 mg, 0.011 mmol), 1,10-diazo Phenanthrene (2 mg, 0.011 mmol), tetrabutylammonium bromide (31 mg, 0.096 mmol) and palladium acetate (1 mg, 0.0045 mmol) were reacted at 70°C under nitrogen for 45 minutes. The temperature was then lowered and ethyl bromoacetate (16 mg, 0.096 mmol) was added and reacted for 10 minutes. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate: petroleum ether = 1:2) to give the title compound (20 mg, yield: 48.1%).

[0676] 2. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl]benzamide

[0677] Lithium borohydride (2 mg, 0.086 mmol) was added to a solution of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-ylphenyl)sulfonyl)acetate (18 mg, 0.028 mmol) in tetrahydrofuran (1 mL) at 25°C and allowed to react for 1 hour. After completion of the reaction, the product was quenched with water, extracted with dichloromethane, concentrated, purified on a silica gel column (ethyl acetate:petroleum ether = 3:2), and slurried with ethyl acetate to obtain the title compound (15 mg, yield: 89.1%).

[0678] Molecular formula: C 28 H 33 F3N6O4S molecular weight: 606.7 LC-MS (M / e): 607.2 (M+H + )

[0679] 1H-NMR (400MHz, CDCl3) δ: 12.70 (s, 1H), 8.56 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 7.92 (s, 1H), 7.86-7.85 (m, 1H), 4.46-4.45 (m, 4H), 4.10-4.09(m,2H),3.44-3.42(m,2H),3.18-3.16(m,4H),2.39(s,4H),2.18-2.16(m,4H),1.90-1.60(m,4H),0.45-0.44(m,4H).

[0680] Example 22 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 28)

[0681] 1. Preparation of 6-bromo-8-iodoimidazole[1,2-a]pyridine

[0682] A 48% aqueous HBr solution (20 mL) was added to anhydrous ethanol (80 mL) containing 5-bromo-3-iodopyridin-2-amine (10.0 g, 33.5 mmol) and 2-bromo-1,1-dimethoxyethane (5.7 g, 33.7 mmol). The reaction was allowed to proceed at 85°C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature to precipitate a solid, which was filtered. The filter cake was dissolved in dichloromethane and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to afford the title compound (9.0 g, yield: 83.3%).

[0683] 2. Preparation of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine

[0684] Select F (9.9 g, 27.9 mmol) was added to 6-bromo-8-iodoimidazole[1,2-a]pyridine (9.0 g, 27.9 mmol) in acetonitrile (40 mL) and allowed to react at 20°C for 0.5 hour. The reaction solution was directly spin-dried, and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (1.8 g, yield: 18.9%).

[0685] 3. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridine

[0686] A mixture of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine (1.8 g, 5.3 mmol), 4,4-difluoropiperidine hydrochloride (1.7 g, 10.9 mmol), Xantphos (636 mg, 1.1 mmol), Pd2dba3 (485 mg, 0.53 mmol), and cesium carbonate (3.4 g, 10.4 mmol) in 1,4-dioxane (50 mL) was reacted at 105°C under nitrogen for 8 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the title compound (1.7 g, 96.4% yield).

[0687] 4. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate

[0688] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridine (1.6 g, 4.8 mmol) was dissolved in 1,4-dioxane (20 mL). T-butyl carbamate (1.1 g, 9.4 mmol) was added, along with (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (800 mg, 0.96 mmol) and cesium carbonate (3.1 g, 9.5 mmol). The reaction was allowed to proceed at 105°C under nitrogen for 3 hours. The reaction was complete. The residue was concentrated to dryness, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (550 mg, yield: 31.0%).

[0689] 5. Preparation of 8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-amine

[0690] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (550 mg, 1.5 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (10 mL), and react at 25°C for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried, and concentrated to afford the title compound (300 mg, yield: 74.7%).

[0691] 6. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0692] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.0 g, 2.9 mmol) in dichloromethane (20 mL). Add thionyl chloride (1.2 g, 10.4 mmol) at 20°C and continue the reaction for 1 hour. After completion, concentrate the reaction mixture to dryness to obtain 1.5 g of crude product, which was used directly in the next step.

[0693] 7. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0694] 2-Fluoro-4-iodobenzoyl chloride (600 mg crude product) was added to a solution of 8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-amine (220 mg, 0.81 mmol) and TEA (324 mg, 3.2 mmol) in dichloromethane (20 mL) at -20°C. The reaction was heated to 45°C and continued for 15 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (75 mg, yield: 15.1%).

[0695] 8. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0696] N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (75 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (23 mg, 0.12 mmol), N-methylglycine (11 mg, 0.12 mmol), potassium phosphate (127 mg, 0.60 mmol), and 2-hydroxyethane-1-sulfonamide (30 mg, 0.24 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was completed. The mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 3:1) to obtain the title compound (40 mg, yield: 53.6%).

[0697] Molecular formula: C 28 H 33 F3N6O4S molecular weight: 606.7 LC-MS (M / e): 607.0 (M+H + )

[0698] 1H-NMR(400MHz,DMSO-d6)δ:11.72(s,1H),10.17(s,1H),8.81(s,1H),7.78(s,1H),7.62(m,1H),7.18(m,1H),7.05(m,1H ),6.88(m,1H),4.95(m,1H),3.84(m,4H),3.34(m,2H),3.13(m,2H),2.97(m,4H),2.11(m,4H),1.55(m,4H),0.34(m,4H).

[0699] Example 23 Preparation of N-(3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 32)

[0700] 1. Preparation of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine

[0701] Select F (9.9 g, 27.9 mmol) was added to acetonitrile (40 mL) containing 6-bromo-8-iodoimidazole[1,2-a]pyridine (9.0 g, 27.9 mmol) and reacted at 20°C for 0.5 hours. The reaction solution was directly spin-dried and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:3) to obtain the target compound (1.8 g, yield: 18.9%).

[0702] 2. Preparation of 6-bromo-3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridine

[0703] A mixture of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine (1.2 g, 3.52 mmol), 2-azaspiro[3.3]heptane hydrochloride (940 mg, 7.04 mmol), Xantphos (407 mg, 0.70 mmol), Pd2dba3 (322 mg, 0.35 mmol), and cesium carbonate (2.3 g, 7.04 mmol) in 1,4-dioxane (20 mL) was reacted at 105°C under nitrogen for 8 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (0.7 g, yield: 64.2%).

[0704] 3. Preparation of tert-butyl (3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)carbamate

[0705] 6-Bromo-3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridine (0.7 g, 2.26 mmol) was dissolved in 1,4-dioxane (30 mL). T-butyl carbamate (529 mg, 4.52 mmol) was added, along with (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (189 mg, 0.23 mmol) and cesium carbonate (2.2 g, 6.78 mmol). The reaction was allowed to proceed at 100°C under nitrogen protection until completion. The product was concentrated to dryness, and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (800 mg crude product).

[0706] 4. Preparation of trifluoroacetic acid salt of 3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-amine

[0707] Dissolve tert-butyl (3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)carbamate (800 mg, 2.31 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (3 mL), and react for 3 hours. After completion of the reaction, remove the solvent under reduced pressure, add MTBE to slurry, filter, and air-dry to obtain the product (600 mg, yield: 75.4%).

[0708] 5. Preparation of N-(3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0709] 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (356 mg, 1.00 mmol) was added to dichloromethane (10 ml), followed by HATU (471 mg, 1.24 mmol) and TEA (420 mg, 4.15 mmol). After stirring for 5 min, 3-fluoro-8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridin-6-amine trifluoroacetate (300 mg, 0.87 mmol) was added. The mixture was stirred at 50° C. for 2 h. The reaction was quenched by adding water, extracted with dichloromethane, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:9) to obtain the title compound (150 mg, yield: 29.4%).

[0710] 6. Preparation of N-(3-fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0711] N-(3-Fluoro-8-(2-azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (49 mg, 0.26 mmol), N-methylglycine (23 mg, 0.26 mmol), potassium phosphate (276 mg, 1.30 mmol) and 2-hydroxyethane-1-sulfonamide (65 mg, 0.52 mmol) were added. Under nitrogen protection, the reaction was carried out at 100 ° C for 2 hours and the reaction was completed. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate: petroleum ether = 3:1) to obtain the product. After concentration, slurry was added with MTBE, filtered, and dried to obtain the desired product (36 mg, yield: 23.1%).

[0712] Molecular formula: C 29 H 35 FN6O4S molecular weight: 582.7 LC-MS (M / e): 583.2 (M+H + )

[0713] 1 H-NMR(400MHz, DMSO-d6)δ:11.67(s,1H),10.13(s,1H),8.48(m,1H),7.80~7.78(m,1H),7.20~7.18(m,1H),7.15(m,1H),7.04~7.01(m, 1H),5.89(m,1H),4.97(m,1H),4.12(m,4H),3.75(m,2H),3.29(m,2H),2.97(m,4H),2.20(m,4H),1.85(m,2H),1.26(m,4H),0.35(m,4H).

[0714] Example 24 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 33)

[0715] 1. Preparation of 6-bromo-8-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoroimidazo[1,2-a]pyridine

[0716] A mixture containing 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine (1.4 g, 4.11 mmol), 4,4-difluorocyclohexene-1-boronic acid pinacol ester (1.3 g, 5.34 mmol), Pd(dppf)Cl2 (300 mg, 0.41 mmol), and K2CO3 (1.7 g, 12.33 mmol) was dissolved in dioxane (30 ml) and water (3 ml). The temperature was raised to 60°C and the reaction was quenched with water. The mixture was extracted with ethyl acetate and concentrated to dryness. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 14:86) to obtain the title compound (900 mg, yield: 66.1%).

[0717] 2. Preparation of tert-butyl (8-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate

[0718] 6-Bromo-8-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoroimidazo[1,2-a]pyridine (0.8 g, 2.42 mmol) was dissolved in 1,4-dioxane (20 mL). T-butyl carbamate (567 mg, 4.84 mmol) was added, along with (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (203 mg, 0.24 mmol) and cesium carbonate (2.4 g, 7.26 mmol). The reaction was allowed to proceed at 100°C under nitrogen until completion. The product was concentrated to dryness, and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to obtain the title compound (500 mg, yield: 56.2%).

[0719] 3. Preparation of tert-butyl (8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate

[0720] Tert-butyl (8-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (420 mg, 1.14 mmol) was dissolved in tetrahydrofuran (10 ml), and Pd / C (230 mg) was added. The reaction was replaced with hydrogen three times. Under hydrogen protection, the mixture was reacted for 4 days, filtered, and the filtrate was concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 15:85) to obtain the title compound (98 mg, yield: 23.3%).

[0721] Preparation of 4-8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-amine

[0722] Dissolve tert-butyl (8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (98 mg, 2.31 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (3 mL), and react for 3 hours. After completion of the reaction, remove the solvent under reduced pressure, extract with dichloromethane, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (85 mg, yield: 13.7%).

[0723] 5. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0724] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.0 g, 2.9 mmol) in dichloromethane (20 mL). Add thionyl chloride (1.2 g, 10.4 mmol) at 20°C and continue the reaction for 1 hour. After completion, concentrate the reaction mixture to dryness to obtain 1.5 g of crude product, which was used directly in the next step.

[0725] 6. Preparation of N-(8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0726] 2-Fluoro-4-iodobenzoyl chloride (600 mg crude product) was added to 8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-amine (85 mg, 0.32 mmol) and TEA (648 mg, 6.4 mmol) in dichloromethane (20 mL) at -20°C. The reaction was heated to 45°C and continued for 15 hours. After completion, the reaction was directly purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain the title compound (110 mg, yield: 56%).

[0727] 7. Preparation of N-(8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0728] N-(8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cuprous iodide (15 mg, 0.08 mmol), N-methylglycine (14 mg, 0.16 mmol), potassium phosphate trihydrate (213 mg, 0.8 mmol), and 2-hydroxyethane-1-sulfonamide (41 mg, 0.33 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was completed. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 50-100%) to obtain the title compound (60 mg, yield: 62%).

[0729] Molecular formula: C 29 H 34 F3N5O4S molecular weight: 605.7 LC-MS (M / e): 606.2 (M+H + )

[0730] 1 H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.95(s,1H),8.00(s,1H),7.62(m,1H),7.28(s,1H),7.08(s,1H),6.85 (m,1H),6.65(m,1H),3.74(m,2H),3.34(m,3H),3.03(m,4H),2.11(m,6H),1.75(m,2H),1.55(m,4H),0.34(m,4H).

[0731] Example 25 Preparation of N-(8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 34)

[0732] 1. Preparation of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine

[0733] Select F (4.8 g, 13.6 mmol) was added to 6-bromo-8-iodoimidazole[1,2-a]pyridine (4.0 g, 12.4 mmol) in acetonitrile (40 mL) and allowed to react at 20°C for 0.5 hour. The reaction solution was directly spin-dried, and the residue was purified on a silica gel column (ethyl acetate / petroleum ether = 40%) to obtain the title compound (1.0 g, yield: 23.8%).

[0734] 2. Preparation of 6-bromo-8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridine

[0735] A mixture of 6-bromo-3-fluoro-8-iodoimidazole[1,2-a]pyridine (700 mg, 2.0 mmol), 4-(difluoromethyl)piperidine hydrochloride (686 mg, 4.0 mmol), Xantphos (231 mg, 0.4 mmol), Pd2dba3 (183 mg, 0.2 mmol), and cesium carbonate (1.9 g, 6.0 mmol) in 1,4-dioxane (10 mL) was reacted at 105°C under nitrogen for 16 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate / petroleum ether = 20%) to obtain the title compound (700 mg, yield: 98.0%).

[0736] 3. Preparation of tert-butyl (8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate

[0737] Dissolve 6-bromo-8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridine (700 mg, 2.0 mmol) in 1,4-dioxane (10 mL), add tert-butyl carbamate (469 g, 4.0 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (335 mg, 0.4 mmol), and cesium carbonate (1.95 g, 6.0 mmol). The reaction was allowed to proceed at 105°C under nitrogen for 5 hours until completion. The residue was concentrated to dryness, and purified on a silica gel column (ethyl acetate / petroleum ether = 30%) to obtain the title compound (280 mg, yield: 36.4%).

[0738] 4. Preparation of 8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-amine

[0739] Dissolve tert-butyl (8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamate (400 mg, 1.0 mmol) in dichloromethane (5 mL). Add trifluoroacetic acid (2 mL) and react at 25°C for 3 hours. Concentrate to obtain the title compound (460 mg crude product).

[0740] 5. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0741] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (410 mg, 1.1 mmol) in dichloromethane (8 mL). Add N,N-dimethylformamide (0.1 mL) and thionyl chloride (410 mg, 3.3 mmol) at 0°C. Continue the reaction for 1 hour. After completion, concentrate the reaction mixture to dryness to obtain 520 mg of crude product, which was used directly in the next step.

[0742] 6. Preparation of N-(8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0743] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (520 mg crude) was added to a solution of 8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-amine (420 mg crude) and TEA (507 mg, 5.0 mmol) in dichloromethane (10 mL) at -20°C. The reaction was heated to 45°C and continued for 18 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate / petroleum ether = 35%) to afford the title compound (120 mg, two-step yield: 18.5%).

[0744] 7. Preparation of N-(8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0745] N-(8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (37 mg, 0.19 mmol), N-methylglycine (17 mg, 0.19 mmol), potassium phosphate (201 mg, 0.95 mmol), and 2-hydroxyethane-1-sulfonamide (48 mg, 0.38 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was completed. The mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate / petroleum ether = 95%) to obtain the title compound (80 mg, yield: 67.0%).

[0746] Molecular formula: C 29 H 35 F3N6O4S molecular weight: 620.7 LC-MS (M / e): 621.2 (M+H + )

[0747] 1 H-NMR(400MHz,DMSO-d6)δ:11.83(s,1H),10.18(s,1H),8.78(s,1H),7.81-7.79(m,1H ),7.33-7.26(m,1H),7.17(s,1H),7.06-7.03(m,1H),6.51-6.46(m,1H),6.11-5.76(m ,1H),4.34-4.19(m,2H),3.77-3.74(m,2H),3.35-3.32(m,2H),3.05-2.98(m,4H),2.9 1-2.87(m,2H),2.15-2.03(m,1H),1.81-1.78(m,2H),1.72-1.58(m,6H),0.36(m,4H).

[0748] Example 26 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 36)

[0749] 1. Preparation of N'-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylformamide

[0750] 5-Bromo-3-iodopyridin-2-amine (10.0 g, 33.5 mmol) was dissolved in DMF (50 mL), and DMF·DMA (20 g, 167.3 mmol) was added. The mixture was allowed to react at 130°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the title compound (11 g, yield: 93%).

[0751] 2. Preparation of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine

[0752] Dissolve N'-(5-bromo-3-iodopyridin-2-yl)-N,N-dimethylformamide (11 g, 33 mmol) in methanol (100 mL), add pyridine (13 g, 165 mmol) and hydroxylamine sulfonate (7.5 g, 66 mmol). React at 25°C for 16 hours. After completion, cool to room temperature, concentrate, extract with dichloromethane, and wash with saturated sodium bicarbonate solution. The dichloromethane layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain the title compound (2.8 g, yield: 26%).

[0753] 3. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine

[0754] A mixture of 6-bromo-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (2.8 g, 8.6 mmol), 4,4-difluoropiperidine hydrochloride (21.7 g, 13.7 mmol), Xantphos (995 mg, 1.7 mmol), Pd2(dba)3 (787 mg, 0.86 mmol), and cesium carbonate (8.4 g, 25.8 mmol) in 1,4-dioxane (50 mL) was reacted at 105°C under nitrogen for 8 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 0-30%) to obtain the title compound (2.4 g, yield: 88%).

[0755] 4. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate

[0756] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine (2.3 g, 7.3 mmol) was dissolved in 1,4-dioxane (40 mL), and tert-butyl carbamate (1.7 g, 14.5 mmol) was added. Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.2 g, 1.5 mmol) and cesium carbonate (7.1 g, 21.9 mmol) were added. The reaction was allowed to proceed at 105°C under nitrogen for 3 hours until completion. The residue was concentrated to dryness, and purified on a silica gel column (ethyl acetate:petroleum ether = 0-40%) to obtain the title compound (1.5 g, yield: 58%).

[0757] 5. Preparation of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-amine

[0758] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate (1.4 g, 4 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and react at 25°C for 2 hours. After completion of the reaction, remove the solvent under reduced pressure, adjust the pH to 8 with saturated sodium bicarbonate, extract with ethyl acetate, dry, and concentrate to obtain the title compound (640 mg, yield: 63%).

[0759] 6. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0760] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.0 g, 2.9 mmol) in dichloromethane (20 mL). Add thionyl chloride (1.2 g, 10.4 mmol) at 20°C and continue the reaction for 1 hour. After completion, concentrate the reaction mixture to dryness to obtain 1.5 g of crude product, which was used directly in the next step.

[0761] 7. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0762] 2-Fluoro-4-iodobenzoyl chloride (600 mg crude product) was added to a solution of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-amine (530 mg, 2.1 mmol) and TEA (648 mg, 6.4 mmol) in dichloromethane (20 mL) at -20°C. The reaction was then heated to 45°C and continued for 15 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford the title compound (600 mg, 48% yield).

[0763] 8. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0764] N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (15 mL). Cuprous iodide (64 mg, 0.33 mmol), N-methylglycine (60 mg, 0.67 mmol), potassium phosphate (892 mg, 4.2 mmol), and 2-hydroxyethane-1-sulfonamide (169 mg, 1.3 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was completed. The mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 50-100%) to obtain the title compound (300 mg, yield: 76%).

[0765] Molecular formula: C 27 H 33 F2N7O4S molecular weight: 589.7 LC-MS (M / e): 590.2 (M+H + )

[0766] 1 H-NMR(400MHz,DMSO-d6)δ:11.67(s,1H),10.17(s,1H),9.20(s,1H),8.40(s,1H),7.82(m,1H),7.18(s,1H),7.05 (m,1H),6.95(s,1H),4.95(m,1H),3.84(m,6H),3.34(m,2H),3.03(m,4H),2.11(m,4H),1.55(m,4H),0.34(m,4H).

[0767] Example 27 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 37)

[0768] 1. Preparation of 6-bromo-8-iodoimidazole[1,2-a]pyridine

[0769] A 48% aqueous HBr solution (40 mL) was added to anhydrous ethanol (80 mL) containing 5-bromo-3-iodopyridin-2-amine (26.7 g, 89.3 mmol) and 2-bromo-1,1-dimethoxyethane (15.0 g, 88.7 mmol). The reaction was allowed to proceed at 85°C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature to precipitate a solid, which was filtered. The filter cake was dissolved in dichloromethane and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to afford the title compound (22.0 g, yield: 76.7%).

[0770] 2. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine

[0771] 6-Bromo-8-iodoimidazole[1,2-a]pyridine (8.0 g, 24.8 mmol), 4,4-difluoropiperidine hydrochloride (7.8 g, 49.6 mmol), Xantphos (2.9 g, 4.96 mmol), Pd2dba3 (2.3 g, 2.48 mmol), and cesium carbonate (40.3 g, 124 mmol) in 1,4-dioxane (80 mL) were reacted at 105°C under nitrogen for 18 hours. After completion, the reaction was directly purified on a silica gel column (ethyl acetate / petroleum ether = 18%) to obtain the title compound (1.9 g, yield: 24.4%).

[0772] 3. Preparation of tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamate

[0773] 6-Bromo-8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine (1.9 g, 6.0 mmol) was dissolved in 1,4-dioxane (20 mL). T-butyl carbamate (1.4 g, 12.0 mmol) was added, along with (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.0 g, 1.2 mmol) and cesium carbonate (9.8 g, 30.0 mmol). The reaction was allowed to proceed at 105°C under nitrogen for 16 hours. The reaction was complete. The residue was concentrated to dryness, and purified on a silica gel column (ethyl acetate / petroleum ether = 45%) to obtain the title compound (650 mg, yield: 31.0%).

[0774] 4. Preparation of 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-amine

[0775] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamate (650 mg, 1.8 mmol) in dichloromethane (10 mL). Add trifluoroacetic acid (6 mL) and react at 25°C for 6 hours. After completion of the reaction, concentrate the mixture to obtain the title compound (730 mg crude product).

[0776] 5. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0777] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (723 g, 2.0 mmol) in dichloromethane (10 mL). Add N,N-dimethylformamide (0.1 mL) and thionyl chloride (714 g, 6.0 mmol) at 0°C. Allow to react for 0.5 hours. After completion, concentrate the reaction mixture to dryness to yield 850 mg of crude product, which was used directly in the next step.

[0778] 6. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0779] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (850 mg crude) was added to 8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-amine (730 mg crude) and TEA (914 mg, 9.0 mmol) in dichloromethane (15 mL) at 0°C. The reaction was heated to 45°C and continued for 16 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate / petroleum ether = 30%) to obtain the title compound (520 mg, two-step yield: 49%).

[0780] 7. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0781] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (420 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (135 mg, 0.71 mmol), N-methylglycine (64 mg, 0.71 mmol), potassium phosphate (753 mg, 3.55 mmol), and 2-hydroxyethane-1-sulfonamide (178 mg, 1.42 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was completed. The product was quenched with water and extracted with ethyl acetate. The residue was concentrated and purified on a silica gel column (ethyl acetate / petroleum ether = 93%) to obtain the title compound (210 mg, yield: 50.2%).

[0782] Molecular formula: C 28 H 34 F2N6O4S molecular weight: 588.7 LC-MS (M / e): 589.2 (M+H + )

[0783] 1 H-NMR(400MHz,DMSO-d6)δ:11.59(s,1H),10.09(s,1H),9.05(s,1H),7.98-7.95(m,1H),7.81-7.79(m,1H),7.45(m,1H),7.15(m,1H),7.04-7 .02(m,1H),6.56(m,1H),4.95(m,1H),3.77-3.76(m,6H),3.34-3.32(m ,2H),2.97-2.89(m,4H),2.18-2.11(m,4H),1.56(m,4H),0.34(m,4H).

[0784] Example 28 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 38)

[0785] 1. Preparation of 5-bromo-2-fluoro-3-iodopyridine

[0786] Dissolve 5-bromo-3-iodopyridin-2-amine (15 g, 50 mmol) in tetrafluoroboric acid (150 mL). Add sodium nitrite (9 g, 130 mmol) in portions at -30°C. Slowly raise the temperature to 0°C and react for 1 hour. Quench with water, filter, and dry the filter cake to obtain the title compound (15 g, yield: 99.4%). 2. Preparation of 5-bromo-2-hydrazino-3-iodopyridine

[0787] Dissolve 5-bromo-2-fluoro-3-iodopyridine (15 g, 49.7 mmol) in ethanol (150 mL), add hydrazine hydrate (13 g, 259 mmol), and react at 70°C for 4 h. Cool to 25°C, filter, and spin-dry the filter cake to obtain the title compound (6.5 g, yield: 41.7%).

[0788] 3. Preparation of 6-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridine

[0789] Dissolve 5-bromo-2-hydrazino-3-iodopyridine (6.5 g, 21 mmol) in acetic acid (60 mL), add triethyl orthoformate (31 g, 210 mmol), and react at 110°C for 1 h. The reaction mixture is spin-dried and adjusted to pH 7-8 by adding saturated aqueous sodium bicarbonate. Filter with suction, and dry the filter cake to obtain the title compound (3.7 g, yield: 54.4%).

[0790] 4. Preparation of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine

[0791] A mixture of 6-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridine (3.7 g, 11 mmol), 4,4-difluoropiperidine hydrochloride (3.4 g, 22 mmol), Xantphos (1.3 g, 2.2 mmol), Pd2dba3 (1.0 g, 1.1 mmol), and cesium carbonate (18 g, 55 mmol) in 1,4-dioxane (80 mL) was reacted at 105°C for 16 hours under nitrogen. After completion, the reaction was purified directly on a silica gel column (ethyl acetate:petroleum ether = 2:1) to obtain the title compound (1.2 g, yield: 34.4%).

[0792] 5. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1,1-diphenylmethaneimine

[0793] A mixture of 6-bromo-8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine (600 mg, 1.9 mmol), diphenylmethaneimine (525 g, 2.9 mmol), Xantphos (220 mg, 0.38 mmol), Pd2dba3 (174 g, 0.19 mmol), and sodium tert-butoxide (548 g, 5.7 mmol) in 1,4-dioxane (30 mL) was reacted at 105°C under nitrogen for 16 hours. After completion, the reaction was purified on a silica gel column (ethyl acetate:petroleum ether = 0-100%) to obtain the title compound (210 mg, yield: 26.5%).

[0794] 6. Preparation of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-amine

[0795] N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1,1-diphenylmethaneimine (200 mg, 0.48 mmol) was dissolved in tetrahydrofuran (3 mL). 2M dilute hydrochloric acid (3 mL) was added and the mixture was reacted at 25°C for 0.5 h. Saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate and purified on a silica gel column (methanol:dichloromethane = 1:10) to obtain the title compound (80 mg, yield: 65.8%).

[0796] 7. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0797] To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (110 mg, 0.31 mmol) in dichloromethane (10 mL) was added N,N-dimethylformamide (0.1 mL) at 25°C. Thionyl chloride (190 mg, 1.6 mmol) was then added at 0°C and the reaction continued for 30 minutes. After completion of the reaction, the reaction solution was concentrated to dryness and used directly in the next step.

[0798] 8. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0799] To a solution of 8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-amine (80 mg, 0.31 mmol) in dichloromethane (10 mL) was added TEA (162 mg, 1.6 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (crude product from the previous step) at 0°C. The reaction was continued at 40°C for 4 hours. After completion, the reaction was concentrated, and the residue was purified on a silica gel column (methanol:dichloromethane = 1:10) to obtain the title compound (60 mg, yield: 32.6%).

[0800] 9. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0801] To a solution of N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.10 mmol) in N,N-dimethylformamide (5 mL) were added cuprous iodide (19 mg, 0.10 mmol), N-methylglycine (18 mg, 0.20 mmol), potassium phosphate (64 mg, 0.30 mmol), and 2-hydroxyethane-1-sulfonamide (38 mg, 0.30 mmol). The mixture was then reacted at 100°C under nitrogen for 3 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate, concentrated, and purified on a silica gel column (methanol:dichloromethane = 1:10) to obtain the title compound (19 mg, yield: 32.2%).

[0802] Molecular formula: C 27 H 33 F2N7O4S molecular weight: 589.7 LC-MS (M / e): 589.9 (M+H + )

[0803] 1H-NMR(400MHz,DMSO-d6)δ:11.60(s,1H),10.10(s,1H),9.30(s,1H),9.06(s,1H),7.75-7.80(m,1H),7.14(s,1H),6.95-7.00(m,1H),6.59(s ,1H),4.90-5.00(m,1H),3.85(s,4H),3.70-3.80(m,2H),3.35-3.40(m ,1H),3.10-3.15(m,4H),2.05-2.20(m,4H),1.23(s,4H),0.34(s,4H).

[0804] Example 29 Preparation of N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 39)

[0805] 1. Preparation of 5,7-dichloroimidazo[1,2-a]pyridine

[0806] Dissolve 4,6-dichloropyridin-2-amine (4.5 g, 27.6 mmol) in anhydrous ethanol (50 mL), add sodium bicarbonate (3.5 g, 41.4 mmol) and chloroacetaldehyde (17.3 g, 221 mmol), and react at 85°C for 3 hours. Concentrate directly, and the residue is purified on a silica gel column (ethyl acetate / petroleum ether = 25%) to obtain the title compound (2.1 g, yield: 40.3%).

[0807] 2. Preparation of 7-chloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine

[0808] A mixture of 5,7-dichloroimidazo[1,2-a]pyridine (2.0 g, 10.7 mmol), 4,4-difluoropiperidine hydrochloride (3.4 g, 21.4 mmol), Xantphos (1.2 g, 2.1 mmol), Pd2dba3 (1.0 g, 1.1 mmol), and cesium carbonate (17.4 g, 53.5 mmol) in 1,4-dioxane (20 mL) was reacted at 105°C under nitrogen for 16 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate / petroleum ether = 35%) to obtain the title compound (960 mg, yield: 33.3%).

[0809] 3. Preparation of tert-butyl (5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)carbamate

[0810] 7-Chloro-5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine (700 mg, 2.6 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl carbamate (609 mg, 5.2 mmol) was added. Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (435 mg, 0.52 mmol) and cesium carbonate (4.2 g, 13.0 mmol) were added. The reaction was allowed to proceed at 105°C under nitrogen for 16 hours until completion. The residue was concentrated to dryness, and purified on a silica gel column (ethyl acetate / petroleum ether = 80%) to obtain the title compound (520 mg, yield: 57.3%).

[0811] Preparation of 4,5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-amine

[0812] Dissolve tert-butyl (5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)carbamate (520 mg, 1.5 mmol) in dichloromethane (10 mL). Add trifluoroacetic acid (5 mL) and react at 25°C for 1 hour. After completion of the reaction, concentrate the mixture to obtain the title compound (650 mg crude product).

[0813] 5. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0814] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (631 mg, 1.77 mmol) in dichloromethane (10 mL). Add N,N-dimethylformamide (0.1 mL) and thionyl chloride (631 g, 5.31 mmol) at 0°C. Allow to react for 0.5 hours. After completion of the reaction, concentrate the reaction mixture to dryness to yield 735 mg of the crude product, which was used directly in the next step.

[0815] 6. Preparation of N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0816] 2-Fluoro-4-iodobenzoyl chloride (735 mg crude) was added to 5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-amine (650 mg crude) and TEA (746 mg, 7.35 mmol) in dichloromethane (20 mL) at 0°C. The reaction was heated to 45°C and continued for 16 hours. After completion, the reaction was purified directly on a silica gel column (ethyl acetate / petroleum ether = 15%) to afford the title compound (200 mg, two-step yield: 22.9%).

[0817] 7. Preparation of N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0818] N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (65 mg, 0.34 mmol), N-methylglycine (30 mg, 0.34 mmol), potassium phosphate (360 mg, 1.7 mmol), and 2-hydroxyethane-1-sulfonamide (85 mg, 0.68 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 3 hours. The reaction was complete. The mixture was quenched with water and extracted with ethyl acetate. The residue was concentrated and purified on a silica gel column (methanol / dichloromethane = 10%) to obtain the title compound (60 mg, yield: 30.2%).

[0819] Molecular formula: C 28 H 34 F2N6O4S molecular weight: 588.67 LC-MS (M / e): 589.2 (M+H + )

[0820] Example 30 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 41)

[0821] 1. Preparation of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfonyl)acetate

[0822] To a solution of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (450 mg, 0.74 mmol) in dimethyl sulfoxide (20 mL) were added potassium metabisulfite (247 mg, 1.1 mmol), sodium formate (111 mg, 1.6 mmol), triphenylphosphine (29 mg, 0.11 mmol), 1,10-phenanthroline (2 0 mg, 0.11 mmol), tetrabutylammonium bromide (358 mg, 1.1 mmol) and palladium acetate (13 mg, 0.058 mmol) were reacted at 70°C under nitrogen for 45 minutes. The temperature was then lowered to 25°C, and ethyl bromoacetate (185 mg, 1.1 mmol) was added and reacted for 10 minutes. After completion of the reaction, the product was quenched with water, extracted with ethyl acetate, and concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:2) to obtain 210 mg of the target compound in a yield of 44.9%.

[0823] 2. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0824] To a solution of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (180 mg, 0.28 mmol) in tetrahydrofuran (10 mL) at 0°C was added lithium borohydride (31 mg, 1.4 mmol) and reacted at 25°C for 1 hour. After completion, the reaction was quenched with water, extracted with ethyl acetate, and concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 2:1) to afford 140 mg of the title compound in an 83.6% yield.

[0825] Molecular formula: C 28 H 32 F3N5O4S molecular weight: 591.7 LC-MS (M / e): 592.2 (M+H + )

[0826] 1H-NMR(400MHz,DMSO-d6)δ:11.0(s,1H),8.66(s,1H),7.83-7.81(m,1H),7.65-7.60(m,2H),7.29-7.27(m,1H),6.66(s,1H),4 .95-4.93(m,1H),3.77-3.70(m,6H),3.55-3.51(m,2H),3.09-3.07(m,4H),2.25-2.05(m,4H),0.60-0.40(m,4H),0.30(s,4H).

[0827] Example 31 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 42)

[0828] 1. Preparation of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfonyl)acetate

[0829] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol) was dissolved in DMSO (10 mL), and potassium metabisulfite (113 mg, 0.51 mmol), sodium formate (46 mg, 0.68 mmol), triphenylphosphine (13 mg, 0.05 mmol), 1,10-phenanthroline (9 mg, 0 051mmol), tetrabutylammonium bromide (164mg, 0.51mmol) and palladium acetate (6mg, 0.027mmol) were reacted at 70°C under nitrogen protection for 45 minutes. The temperature was lowered and ethyl bromoacetate (85mg, 0.51mmol) was added. The reaction was continued at 25°C for 10 minutes. After completion of the reaction, water was added to quench the reaction. The product was extracted with ethyl acetate and concentrated. The residue was purified on a silica gel column (ethyl acetate: petroleum ether = 1:1) to obtain the target compound (30mg, yield: 14.3%).

[0830] 2. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0831] Lithium borohydride (5.7 mg, 0.025 mmol) was added to a solution of ethyl 2-((4-((8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (30 mg, 0.049 mmol) in tetrahydrofuran (10 mL) at 0°C and allowed to react at 25°C for 1 hour. After completion, the reaction was quenched with water, extracted with ethyl acetate, and purified on a preparative plate (100% ethyl acetate) to obtain the title compound (17 mg, yield: 60.4%).

[0832] Molecular formula: C 28 H 33 F2N5O4S molecular weight: 573.66 LC-MS (M / e): 574.2 (M+H + )

[0833] 1 H-NMR(400MHz,DMSO-d6)δ:11.01(s,1H),9.17(s,1H),8.10-8.20(s,1H),7.70-7.80(m,1H),7.55-7.65(m,2H),3.70 -3.75(m,2H),3.45-3.50(m,6H),3.00-3.10(m,4H),2.10-2.30(m,4H),1.90-2.05(m,2H),1.46(s,4H),0.30(s,4H).

[0834] Example 32 Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 43)

[0835] 1. Preparation of 8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-amine

[0836] Dissolve tert-butyl (8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)carbamate (200 mg, 0.54 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react at 20°C for 1 hour. After completion of the reaction, remove the solvent under reduced pressure, extract with dichloromethane, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude target compound, which is used directly in the next step.

[0837] 2. Preparation of 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride

[0838] Dissolve 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (193 mg, 0.54 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL). Add thionyl chloride (196 mg, 1.6 mmol) at 0°C and continue the reaction for 30 minutes. After completion of the reaction, concentrate the reaction mixture to dryness to obtain the crude product, which was used directly in the next step.

[0839] 3. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0840] 2-Fluoro-4-iodobenzoyl chloride (crude) was added to 8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-amine (crude) and TEA (328 mg, 3.2 mmol) in dichloromethane (10 mL) at 0°C and the reaction continued for 30 minutes. After completion of the reaction, water was added, and the organic phase was extracted with dichloromethane. The resulting mixture was dried, concentrated, and purified on a silica gel column (ethyl acetate:petroleum ether = 1:4) to afford 20 mg of the title compound, with a two-step yield of 6.1%.

[0841] 4. Preparation of N-(8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0842] N-(8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (20 mg, 0.033 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (6 mg, 0.032 mmol), N-methylglycine (6 mg, 0.067 mmol), potassium phosphate (35 mg, 0.16 mmol), and 2-hydroxyethane-1-sulfonamide (12 mg, 0.096 mmol) were added. The reaction was allowed to proceed at 100°C under nitrogen for 10 hours. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, concentrated, and purified by TLC (ethyl acetate:petroleum ether = 4:1) to obtain 5 mg of the title compound in a yield of 25.1%.

[0843] Molecular formula: C 27 H 32 F3N7O4S molecular weight: 607.7 LC-MS (M / e): 608.2 (M+H + )

[0844] 1 H-NMR(400MHz,DMSO-d6)δ:11.85(s,1H),10.14(s,1H),8.14-8.13(m,1H), 7.94-7.89(m,1H),7.73-7.72(m,1H),7.23-7.22(m,1H),7.09-7.06(m,1H), 4.95-4.92(m,1H),4.40-4.30(m,4H),3.76-3.73(m,2H),3.35-3.31(m,2H), 3.05-2.95(m,4H),2.09-2.05(m,4H),1.80-1.70(m,4H),0.40-0.37(m,4H).

[0845] The compounds shown in the following table were prepared using the same or similar methods as in the above examples:

[0846] The KIF18A inhibitors and their applications provided by the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above examples is only intended to help understand the methods and central ideas of the present invention. It should be noted that, for those of ordinary skill in the art, several improvements and modifications may be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection of the claims of the present invention.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof, in, X 1 、X 4 are independently selected from N or CR a ; X 2 With X 3 The connection between them is single bond or double bond; When X 2 With X 3 When the connection mode between is single key, X 2 、X 3 are independently selected from N or C; when X 2 With X 3 When the connection between them is a double bond, X 2 、X 3 All are C; Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl; R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl, 5-12 membered bridged heterocyclyl, optionally substituted with one or more substituents Q2; R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH2, -S(O)2-NH2, -(L) optionally substituted with one or more substituents Q3 m -C 1-6 Alkyl, -(L) m -C 2-6 Alkenyl, -(L) m -C 2-6 Alkynyl, -(L) m -C 1-6 Alkoxy, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -5-12 membered spirocyclic group, -(L) m -5-12 membered spiroheterocyclic group, -(L) m -5-12 membered bridged ring group, -(L) m -5-12 membered bridged heterocyclic group; Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, -C(O)-NH2, C 1-6 Alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, optionally substituted by 1-4 substituents q, wherein the substituents q are independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -; Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminoacyl, C 1-6 Alkyl amido, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -(L) m -6-10 membered aryl, -(L) m -5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl or -(L) m -3-8 membered heterocyclic group; Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; Each m and n is independently an integer of 0-6.

2. The compound according to claim 1, its pharmaceutically acceptable salt, ester or stereoisomer thereof, in, Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl; R 1 substituted with 1-4 substituents Q2, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, 7-11 membered spiro Cycyl, 7-11 membered spiroheterocyclyl; R 2 、R 5 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclyl; R 3 、R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted with 1 to 4 substituents Q3 -(L) m -C 1-6 Alkyl, -(L) m -C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 alkyl; R 6 Selected from -C(O)N(R c )2、-N(R c )S(O)2-C 1-6 Alkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered heterocyclic group, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered heterocyclic group, -S(O)2-C 1-6 alkyl, -S(O)2-3-6 membered cycloalkyl, -S(O)2-3-6 membered heterocyclic group, -S(O)(NR c )-C 1-6 Alkyl, -S(O)(NR c )-3-6 membered cycloalkyl, -S(O)(NR c )-3-6 membered heterocyclic group, -N(R c )C(O)-C 1-6 Alkyl, -N(R c )C(O)-3-6 membered cycloalkyl, -N(R c )C(O)-3-6 membered heterocyclic group, -C(O)N(R c )-C 1-6 Alkyl, -C(O)N(R c )-3-6 membered cycloalkyl, -C(O)N(R c )-3-6 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-3-6 membered cycloalkyl, -C(O)-3-6 membered heterocyclic group, -N(R c )-C 1-6 alkyl; Each L is independently selected from -C(O)-, -S(O)-, -S(O)2-, -NR c -、-S(O)(NR c )-、-CR a1 R b -; Each R a , each R a1 , each R b are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, haloC 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino; Each of m and n is independently an integer of 0-4.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl; R 1 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl or 5-6 membered heteroaryl, which are optionally substituted with 1-3 substituents Q2; R 2 、R 5 Each is independently selected from hydrogen, a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl optionally substituted with 1-3 substituents Q3; R 3 、R 4 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; R 6 Selected from -N(R c )S(O)2-C 1-6 Alkyl, -S(O)2N(R c )-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -N(R c )S(O)2-3-6 membered cycloalkyl, -S(O)2N(R c )-3-6 membered cycloalkyl, -N(R c )-C 1-6 alkyl; Each R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; Each R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, carboxyl C 1-6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, in, Selected from the following structures, Each R a , each R 1 , each Q1, each n is defined as described in any one of claims 1-3.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, which has a structure represented by formula (II'), in, n is 0, 1, or 2; X 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , each R a , each Q1 is defined as described in any one of claims 1-4.

6. The compound according to claim 5, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: X 1 Select N or CR a ; R 1 is selected from a 3-6 membered cycloalkyl group, a 7-8 membered spiroheterocyclyl group or a 3-6 membered nitrogen-containing heterocyclyl group optionally substituted by 1-3 substituents Q2; R 2 、R 5 Each is independently selected from hydrogen, a 5-6 membered nitrogen-containing heterocyclic group or a 7-9 membered nitrogen-containing spiroheterocyclic group optionally substituted by 1-3 substituents Q3; R 3 、R 4 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy; R 6 -NHS(O)2-C optionally substituted with 1-4 substituents Q3 1-6 Alkyl, -S(O)2NH-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-3-6 membered cycloalkyl, -NH-C 1-6 alkyl; Each R a are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, haloC 1-4 Alkyl, halogenated C 1-4 alkoxy; Each Q1, each Q2, each Q3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, carboxyl C 1-4 alkyl; n is 0, 1, or 2.

7. A compound represented by general formula (I'), a pharmaceutically acceptable salt, ester or stereoisomer thereof, in, X 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 5 、R 6 , each R a , each Q1 is defined as described in any one of claims 1-6.

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

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

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

11. Use of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, ester or stereoisomer thereof, or the pharmaceutical preparation according to claim 9, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating and / or preventing KIF18A-mediated diseases and related diseases.

12. The use according to claim 11, wherein The KIF18A-mediated disease and related diseases are selected from 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 tumors.

13. A method for preparing the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, comprising the following steps: The compound of formula (II'-1) is reacted with the compound of formula (II'-2) to obtain the compound of formula (II'-3); the compound of formula (II'-3) is reacted with R 6 -H reaction to obtain a compound of formula (II'); Wherein, X is a halogen; X 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , each R a , n, each Q1 is defined as described in any one of claims 1-8.

14. Compounds having the following structure: in, Each X is independently halogen; each X 1 , each R 1 , each R 2 , each R 3 , each R 4 , each R 5 , each R 6 , each R a , each n, each Q1 is defined as described in any one of claims 1-8.

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