Fused heterocyclic compounds and uses thereof

Abstract

The present application relates to the technical field of medicine, in particular to a fused heterocyclic compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and preparation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and the use of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in the preparation of a drug for treating and / or preventing a proliferative disease, an immunological disease or an inflammatory disease.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to fused heterocyclic compounds, their pharmaceutically acceptable salts, their esters or stereoisomers, pharmaceutical compositions and formulations containing said compounds, their pharmaceutically acceptable salts, their esters or stereoisomers, methods for preparing said compounds, their pharmaceutically acceptable salts, their esters or stereoisomers, and the use of said compounds, their pharmaceutically acceptable salts, their esters or stereoisomers in the preparation of medicaments for treating and / or preventing proliferative diseases, immune diseases, and inflammatory diseases. Background Technology

[0002] Histone-lysine N-methyltransferase 2 (KMT2) family proteins 4-methylate the lysine residues at the tail of histone H3 in important regulatory regions of the genome, thereby playing a crucial role in regulating chromatin structure and DNA accessibility. The human KMT2 family is also known as the mixed lineage leukemia (MLL) protein family.

[0003] The MLL gene, located on chromosome 11q23, is highly susceptible to rearrangement. Currently, over 80 genes have been identified that fuse with MLL genes, commonly including AF4, AF9, AF10, ENL, AF6, and ELL. MLL gene rearrangements occur in approximately 5% of acute lymphoblastic leukemia (ALL), approximately 5-10% of adult acute myeloid leukemia (AML), 10% of childhood acute AML, 70%-80% of infantile acute AML, and almost all mixed lineage (or dual-phenotype) leukemia (MLL) cases. MLL rearrangements are a strong predictor of poor prognosis in leukemia patients; current treatments have low efficacy, and the 5-year overall survival rate is 10-35%.

[0004] Menin is the expression product of the multiple endocrine neoplasia 1 (MEN1) gene, located in the cell nucleus. As a scaffold protein, it plays multiple crucial roles in biological pathways such as cell growth regulation, cell cycle control, genome stability, bone development, and hematopoiesis. In MLL-rearranged leukemia, Menin is considered a key oncogenic cofactor of MLL, participating in the regulation of tumor cell proliferation and differentiation. When the MLL gene undergoes translocation and rearrangement mutations, the corresponding MLL fusion protein is expressed intracellularly. This fusion protein interacts with the Menin protein, thereby activating its downstream genes, such as HOX (homeotype gene) and MEIS1 (mixed lineage leukemia proto-oncogene), promoting leukemia development. In pancreatic islet cells, Menin mutations lead to excessive β-cell proliferation, resulting in pancreatic β-cell tumors. Excessive Menin expression can inhibit β-cell proliferation, leading to relative insulin insufficiency and promoting diabetes.

[0005] Nucleophosmin 1 (NPM1) and nucleoporin 98 (NUP98), which are 98 kDa nucleoporin, also contribute to leukemia development through the interaction of Menin and MLL, and are associated with the upregulation of HOXA and MEIS1. NPM1 mutations are the most common genetic alterations in adult AML, accounting for approximately 20%-30%. The frequency of NUP98 rearrangements is low in adult AML patients (approximately 1%-2%), but the frequency of NUP8 rearrangements is 35% in patients with 11p15 abnormalities. The frequency of NUP98 rearrangements is even higher in childhood AML, with this translocation present in 6% to 10% of cases.

[0006] MYC is a transcription factor involved in tumorigenesis, typically regulating genes related to cell proliferation, differentiation, and apoptosis. Aberrant expression of MYC can be caused by a variety of factors, including activation of RAS. Its activity largely depends on its interaction with Menin. Aberrant expression is found in various tumors, including DLBCL, MM, and KRAS-mutated solid tumors (colon cancer, pancreatic cancer, and lung cancer), playing a key role in tumorigenesis and development.

[0007] Therefore, inhibiting the interaction between Menin and MLL, or influencing the effects of MYC or KRAS by inhibiting Menin, will become an effective treatment for hematologic malignancies, lymphomas, and solid tumors. However, the effectiveness of compounds currently under investigation is limited, and there is an urgent need to develop compounds with strong inhibitory effects, broad action range, and novel structures. Summary of the Invention

[0008] The purpose of this invention is to provide a fused heterocyclic compound and its applications. The specific technical solution is as follows:

[0009] In some embodiments, the present invention first provides compounds of general formula (I), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof:

[0010]

[0011] Among them, Z1, Z2, Z3, and Z4 are independently selected from CR. a Or N;

[0012] X1, X2, and X4 are each independently selected from N or CR. a ;

[0013] X3 is selected from S, O, NR c or CR a R b ;

[0014] X5 is selected from N or CR2;

[0015] Y1 is selected from CH or N;

[0016] Y2 is selected from O and CR. a1 R b1 or NR c1 ;

[0017] Y3 is selected from CR a3 Or N;

[0018] Y4 is selected from CR a4 Or N;

[0019] Y5 is selected from CR a5 R b5 C(O), S(O)2, O, S or NR c5 ;

[0020] Y6 is selected from CR a6 R b6 C(O), S(O)2, O, S or NR c6 ;

[0021] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl;

[0022] Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R)-. c2 )-、-C(R a2 (R) b2 )-;

[0023] R a1 Rb1 Each is independently selected from hydrogen, cyano, halogen, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -C(R a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ), -N(R c3 )-S(O)2-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-S(O)2-C(R a3 )=C(R a3 (R) b3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), -S(O)-C(R) a3 )=C(R a3 (R) b3 ), -OC(R a3 (R) b3 )-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(R a3 (R) b3 )-C(R a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl groups are optionally surrounded by one or more halogens, cyano groups, or C groups. 1-6 Alkyl substitution;

[0024] Each R c Each R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and 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, -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0025] Each R1, R2, each R3, each R a Each R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, -C(O)-NH2, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl;

[0026] m and q are independent integers from 0 to 4;

[0027] n is an integer between 1 and 4.

[0028] In some implementations, X1 and X2 are each independently selected from N.

[0029] In some implementations, X3 is selected from NR c or CR a R b .

[0030] In some implementations, X3 is selected from NH.

[0031] In some implementations, X4 is selected from N or CR. a .

[0032] In some implementations, X4 is selected from CH.

[0033] In some implementations, Y1 is selected from CH or N; Y2 is selected from O or CR. a1 R b1 or NR c1 .

[0034] In some implementations, Y1 is selected from CH.

[0035] In some implementations, Y2 is selected from CR a1 R b1 or NR c1 .

[0036] In some implementation schemes, Y3 and Y4 are independently selected from CR. a .

[0037] In some implementations, Y3 and Y4 are each independently selected from CH.

[0038] In some implementation schemes, Y5 and Y6 are independently selected from CR. a R b or NR c .

[0039] In some implementations, Y5 and Y6 are each independently selected from CH2.

[0040] In some implementations, Z1, Z2, Z3, and Z4 are each independently selected from CR a .

[0041] In some implementations, Z1, Z2, Z3, and Z4 are each independently selected from CH.

[0042] In some embodiments, ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclic, 6-10 membered aryl, or 5-8 membered heteroaryl.

[0043] In some embodiments, ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl.

[0044] In some embodiments, ring A is selected from 5-6 membered nitrogen-containing heterocyclic groups or phenyl groups.

[0045] In some embodiments, ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanecyclohexyl, 1,3-dioxanecyclohexyl, 1,3-dioxanecyclopentyl, 1,4-dioxanecyclohexadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazoyl, 4,5-dihydroimidazoyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazoyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrroleyl, pyrazolyl, imidazoyl.

[0046]

[0047] In some embodiments, ring A is selected from piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridineyl, pyridazinyl, pyrroleyl, pyrazolyl, imidazolyl, etc.

[0048]

[0049] In some embodiments, ring A is selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, and other groups.

[0050]

[0051] In some implementations, each L is independently selected from -C(O)-, -N(R)-, etc. c2 )-、-C(R a2 (R) b2 )-、-S(O)2-.

[0052] In some implementations, -(L)n- is selected from the following structures: -N(R c2 -C(O)-、-N(R) c2 )-C(O)-N(R c2 )-、-N(R c2 )-C(O)-C(R a2 (R) b2 )-、-N(R c2 -S(O)2-、-N(R) c2 )-C(R a2 (R) b2 )-、-C(R a2 (R) b2 -C(O)-, -C(R) a2 (R) b2 )-C(R a2 (R) b2 )-、-C(O)-N(R c2 )-.

[0053] In some implementations, -(L)n- is selected from the following structures: -N(H)-C(O)-, -N(H)-C(O)-N(H)-, -N(H)-C(O)-CH2-, -N(H)-S(O)2-, -N(H)-CH2-, N(CH3)-CH2-, -CH2-C(O)-, -N(CH3)-C(O)-, -CH2-CH2-, -C(O)-N(H)-.

[0054] In some implementations, -(L)n- is selected from -CH2-CH2-.

[0055] In some implementations, R a1 R b1 Each is independently selected from hydrogen, cyano, halogen, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -C(R a3 (R) b3 )-N(R C3 )-C(O)-C(Ra3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-3 halogen, cyano, or C groups. 1-6 Alkyl substitution.

[0056] In some implementations, R a1 R b1 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-2 halogen, cyano, or C groups. 1-6 Alkyl substitution.

[0057] In some implementations, R a1 R b1 Each is independently selected from hydrogen, cyano, and C. 1-4 Alkyl, -C(R) a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R)b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-4 Alkyl groups are optionally surrounded by 1-2 halogen, cyano, or C groups. 1-4 Alkyl substitution.

[0058] In some implementations, R a1 R b1 Each is independently selected from hydrogen, cyano, and -C(R) groups. a3 (R) b3 -C(O)-CH=CH2、-C(R) a3 (R) b3 )-N(R c3 -C(O)-CH=CH2、-N(R) c3 -C(O)-CH=CH2、-C(O)-C 1-4 Alkyl, -C(O)-H, -C(O)-CH=CH2, -N(R) c3 )-C(O)-C 1-4 Alkyl, -N(R) c3 -C(O)-H, -N(R) c3 (R) c4 -C(O)-C 1-4 Alkyl group.

[0059] In some implementations, R a1 R b1The groups are independently selected from hydrogen, cyano, -CH2-N(H)-C(O)-CH=CH2, -CH2-N(CH3)-C(O)-CH=CH2, -N(H)-C(O)-CH=CH2, -N(CH3)-C(O)-CH=CH2, -C(O)-CH3, -C(O)-H, -C(O)-CH=CH2, -N(H)-C(O)-CH3, -N(H)-C(O)-CH2CH3, -N(H)-C(O)-H, -N(CH3)-C(O)-CH2CH3, -N(CH3)-C(O)-CH3, -N(H)-CN, -N(CH3)-CN, -C(O)-O-CH3, and -C(O)-O-CH2CH3.

[0060] In some implementations, each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl.

[0061] In some implementations, each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino.

[0062] In some implementations, each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and 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, C 1-4 alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonylamino.

[0063] In some implementations, each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl.

[0064] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0065] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0066] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, -C(O)-R a3 -C(O)-CH2-R a3 -C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C CH、-C(O)-C C(CH3), -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-4 Alkyl, C 1-4The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl group.

[0067] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each of the following groups is independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -C(O)-R a3 -C(O)-CH2-R a3 -C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C CH、-C(O)-C C(CH3), -S(O)2-R a3 -S(O)2-CH=CH2, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, and isopropoxy groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkyl group.

[0068] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6The radicals are independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH2-CN, -C(O)-CH(CH3)-CN, -CH2-CN, -CH(CH3)-CN, -C(O)-CH=CH2, -C(O)-C(F=CH2), -C(O)-C(Cl=CH2, -C(O)-C CH、-C(O)-C C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3.

[0069] In some implementations, R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH2-CN, -C(O)- CH(CH3)-CN, -CH2-CN, -CH(CH3)-CN, -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C CH、-C(O)-C C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3.

[0070] In some implementations, m and q are independent integers from 0 to 3; n is an integer from 1 to 3.

[0071] In some implementations, m and q are independently 0, 1, and 2, respectively; n is 1, 2, or 3.

[0072] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (II):

[0073]

[0074] in,

[0075] X1, X2, and X4 are each independently selected from N or CR. a ;

[0076] X3 is selected from S, O, NR c or CR a R b ;

[0077] Y1 is selected from CH or N;

[0078] Y2 is selected from O and CR. a1 R b1 or NR c1 ;

[0079] Y3 is selected from CR a3 ;

[0080] Y4 is selected from CR a4 ;

[0081] Y5 is selected from CR a5 R b5 or NR c5 ;

[0082] Y6 is selected from CR a6 R b6 or NR c6 ;

[0083] Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclic, 6-10 membered aryl, and 5-8 membered heteroaryl;

[0084] Each L is independently selected from -C(O)- and -N(R)-. c2 )-、-C(R a2 (R) b2 )-、-S(O)2-;

[0085] R a1 R b1 Each is independently selected from hydrogen, cyano, halogen, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -C(R a3 (R) b3 )-N(R C3 )-C(O)-C(R a3 )=C(R a3 (R)b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-3 halogen, cyano, or C groups. 1-6 Alkyl substitution;

[0086] R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0087] Each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl;

[0088] m and q are independent integers from 0 to 4;

[0089] n is an integer between 1 and 4.

[0090] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (III):

[0091]

[0092] X3 is selected from NR c or CR a R b ;

[0093] Y1 is selected from CH or N;

[0094] Y2 is selected from CR a1 R b1 or NR c1 ;

[0095] Y3 is selected from CR a3 ;

[0096] Y4 is selected from CR a4 ;

[0097] Y5 is selected from CR a5 Rb5 ;

[0098] Y6 is selected from CR a6 R b6 ;

[0099] Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0100] Each L is selected independently -C(R) a2 (R) b2 )-;

[0101] R a1 R b1 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-2 halogen, cyano, or C groups. 1-6 Alkyl substitution;

[0102] R c R c1 Each R c3 Each R c4 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0103] Each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide;

[0104] m and q are independent integers from 0 to 3;

[0105] n is an integer between 1 and 3.

[0106] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (IV):

[0107]

[0108] Ring A, each of R1, R2, each of R3, R a R a3 R a4 R a5 R a6 Rb5 R b6 R c R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0109] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (IV):

[0110] Ring A is selected from 5-6 membered heterocyclic groups, phenyl groups, or 5-6 membered heteroaryl groups;

[0111] R c R c1 Each is independently selected from hydrogen, cyano, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, -C(O)-R a3 -C(O)-CH2-R a3 -C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C CH、-C(O)-C C(CH3), -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-4 Alkyl, C 1-4 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0112] Each R1, R2, each R3, R a Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C1-4 Alkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, C 1-4 alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonamide;

[0113] m and q are independently 0, 1, and 2, respectively.

[0114] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (V):

[0115]

[0116] Ring A, each of R1, R2, each of R3, R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0117] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (V):

[0118] Wherein ring A is selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, and other groups.

[0119]

[0120] Each R1, R2, and each R3 is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide;

[0121] R c1Selected from hydrogen, cyano, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH2-CN, -C(O)-CH(CH3)-CN, -CH2-CN, -CH(CH3)-CN, -C(O)-CH=CH2, -C(O)-C(F=CH2, -C(O)-C(Cl=CH2, -C(O)-C CH、-C(O)-C C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3;

[0122] m and q are independently 0, 1, and 2, respectively.

[0123] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (VI):

[0124]

[0125] Ring A, each of R1, R2, each of R3, R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0126] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (VII):

[0127]

[0128] Ring A, each of R1, R2, each of R3, R a R a3 R a4 R a5 R a6 R b5 R b6 R c R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0129] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (VII):

[0130] Wherein, ring A is selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, and other groups.

[0131]

[0132] R c R c1 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0133] Each R1, R2, each R3, R a R a3 R a4 R a5 R a6 R b5 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide;

[0134] m and q are independently 0, 1, and 2, respectively.

[0135] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (VIII):

[0136]

[0137] Each R1, R2, each R3, R a R a3 R a4 R a5 R a6 R b5 R b6 R c R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0138] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure as shown in formula (IX):

[0139]

[0140] Each R1, R2, each R3, R a R c R c1 The definitions of m and q are as described in any of the aforementioned schemes.

[0141] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein,

[0142] Ring A is selected from 5-6 membered heterocyclic groups, phenyl groups, or 5-6 membered heteroaryl groups;

[0143] R c1 Selected from hydrogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, -C(O)-R a3 -C(O)-CH2-R a3 -C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C CH、-C(O)-C C(CH3), -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C1-4 Alkyl, C 1-4 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0144] Each R1, R2, each R3, each R a3 Each R b3 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and 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, C 1-4 alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonamide;

[0145] m and q are independently 0, 1, and 2, respectively.

[0146] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein,

[0147] Ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxacyclohexyl, 1,3-dioxacyclohexyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclohexadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazoyl, 4,5-dihydroimidazoyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazoyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridine, pyridazinyl, pyrroleyl, pyrazolyl, imidazoyl

[0148]

[0149] -(L)n- is selected from -CH2-CH2-;

[0150] R a1 R b1 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-N(R c3 )-C(O)-C(R a3)=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-2 halogen, cyano, or C groups. 1-6 Alkyl substitution;

[0151] Each R1, R2, each R3, R a R b Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide;

[0152] R c R c1 Each R c3 Each R c4 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(Ra3 (R) b3 -C(O)-C C(R a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0153] In some embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein,

[0154] Ring A is selected from piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridineyl, pyridazinyl, pyrroleyl, pyrazolyl, imidazolyl, etc.

[0155]

[0156] Each R1, R2, each R3, R a Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0157] R c R c1The radicals are independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH2-CN, -C(O)-CH(CH3)-CN, -CH2-CN, -CH(CH3)-CN, -C(O)-CH=CH2, -C(O)-C(F=CH2), -C(O)-C(Cl=CH2, -C(O)-C CH、-C(O)-C C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3.

[0158] In some embodiments of the present invention, the structures of the provided compounds, their pharmaceutically acceptable salts, esters, or stereoisomers are shown below:

[0159]

[0160]

[0161] The present invention also provides a pharmaceutical composition comprising a compound represented by the foregoing general formula, a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutic agents, optionally further comprising one or more pharmaceutical carriers and / or diluents.

[0162] The second therapeutic active agent described in this invention includes, but is not limited to, immune checkpoint inhibitors, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotic agents, antihormones, and anticancer drugs.

[0163] The present invention also provides a pharmaceutical formulation comprising a compound represented by the aforementioned general formula, a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical formulation being any clinically or pharmaceutically acceptable dosage form.

[0164] In some embodiments of the present invention, the above-described pharmaceutical preparations can be administered to patients or subjects requiring such treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When formulating oral preparations, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the above-described pharmaceutical preparations can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectable preparations, conventional methods in the existing pharmaceutical field can be used. When preparing injectable preparations, excipients may not be added, or suitable excipients may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays, etc.

[0165] The pharmaceutical carriers and / or diluents used in the pharmaceutical compositions or formulations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical formulation. The selection of a specific carrier and / or diluent will depend on the route of administration or the type and state of disease for treating a particular patient. The preparation method of a suitable pharmaceutical composition for a specific route of administration is entirely within the knowledge of those skilled in the art of pharmaceuticals. For example, pharmaceutical carriers and / or diluents may include solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc., conventional in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners, etc., may also be added to the pharmaceutical composition.

[0166] The present invention also provides the use of the compounds represented by the foregoing general formula, their pharmaceutically acceptable salts, esters or stereoisomers thereof, the foregoing pharmaceutical preparations or the foregoing pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of proliferative diseases, immune diseases, and inflammatory diseases.

[0167] The present invention also provides a method for treating a disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound represented by the aforementioned general formula, a pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a proliferative disease, an immune disease or an inflammatory disease.

[0168] The proliferative diseases are selected from cancers or benign tumors, including but not limited to hematologic malignancies, colorectal cancer, gastric cancer, ovarian cancer, breast cancer, endometrial cancer, cervical cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, prostate cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bladder cancer, testicular cancer, skin cancer, and bone cancer; the hematologic malignancies include but are not limited to leukemia, multiple myeloma, and malignant lymphoma; the lung cancers include but are not limited to small cell lung cancer and non-small cell lung cancer; the brain cancers include but are not limited to glioma, neuroblastoma, astrocytoma, and meningioma.

[0169] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and its chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0170] In this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this application differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this application shall prevail.

[0171] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

[0172] In this invention, "halogenation" means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen" is as defined above.

[0173] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C". 1-5 Alkyl", C 1-4 Alkyl", C 1-3 Alkyl", C 1-2 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 2-4 Alkyl", C 2-3 Alkyl", C 3-6 Alkyl", C 3-5 Alkyl", C 3-4 Alkyl", C 4-6 Alkyl", C 4-5 Alkyl", C 5-6Alkyl groups, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C" in this invention... 1-4 "alkyl" refers to C 1-6 Specific examples of alkyl groups containing 1-4 carbon atoms.

[0174] The "C" described in this invention 2-6 "Alkenyl" refers to a straight-chain, branched, or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C". 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", etc., specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl -1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, etc.

[0175] The "C" described in this invention 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-6 carbon atoms with a triple bond, including, for example, "C". 2-5 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3"Alynyl", etc., specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.

[0176] The “C” mentioned in this article 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 alkylsulfonyl, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminosulfonyl, C 1-6 alkyl carbonyl, C 1-6 "alkyloxycarbonyl" refers to a group with C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, C 1-6 Alkyl-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 A group formed in the alkyl-OC(O)- manner, wherein "C" 1-6 The definition of "alkyl" is as described above.

[0177] The “C” mentioned in this article 1-4 Alkoxy, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 alkylsulfonyl, C 1-4 Alkylsulfonamide, C 1-4 Alkylaminosulfonyl, C 1-4 alkyl carbonyl, C 1-4 "Alkoxycarbonyl" refers to a group with C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 Alkyl)2-N-, C 1-4 Alkyl-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 A group formed in the alkyl-OC(O)- manner, wherein "C"1-4 The definition of "alkyl" is as described above.

[0178] The "halogenated C" mentioned in this article 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, Halogenated C 1-6 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups that respectively replace C. 1-6 Alkyl, C 1-6 A group formed by the hydrogen atom in an alkoxy group.

[0179] The "halogenated C" mentioned in this article 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, Halogenated C 1-4 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups that respectively replace C. 1-4 Alkyl, C 1-4 A group formed by the hydrogen atom in an alkoxy group.

[0180] The "3-10 membered cycloalkyl" mentioned in this invention refers to a saturated or partially saturated cycloalkyl group containing 3-10 carbon atoms that is non-aromatic, including "monocycloalkyl" and "fused cycloalkyl". "Monocycloalkyl" refers to a saturated or partially saturated monocycloalkyl group that is non-aromatic, including "3-10 membered saturated cycloalkyl" and "3-10 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "3-8 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", etc. “6-7 membered cycloalkyl”, “6-8 membered cycloalkyl”, “7-8 membered cycloalkyl”, “3-6 membered saturated cycloalkyl”, “4-7 membered saturated cycloalkyl”, “4-8 membered saturated cycloalkyl”, “5-8 membered saturated cycloalkyl”, “5-7 membered saturated cycloalkyl”, “5-6 membered saturated cycloalkyl”, “3-6 membered partially saturated cycloalkyl”, “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 include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cycloheptenyl-1,3-diene, cycloheptenyl-1,4-diene, cycloheptenyl-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-diene, cyclooct-1,4-diene, cyclooct-1,5-diene, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.Wherein, "fused cyclic alkyl" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring of the fused ring may be an aromatic ring, but the fused ring as a whole does not possess aromaticity; examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrene, bicyclo[3. [1.0] Hex-2-enyl, bicyclo[4.1.0] hept-3-enyl, bicyclo[3.2.0] hept-3-enyl, bicyclo[4.2.0] oct-3-enyl, 1,2,3,3a-tetrahydrocyclopentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,8a-decahydrophenanthrene, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

[0181] The "3-10 membered heterocyclic group" described in this invention refers to a saturated or partially saturated monocyclic or fused-ring group that contains at least one heteroatom (e.g., 1, 2, 3, 4, or 5) and has 3-10 ring atoms, and is non-aromatic. The heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the ring structure can be substituted with oxygen. This includes both "3-10 membered saturated heterocyclic groups" and "3-10 membered partially saturated heterocyclic groups." Preferably, the "3-10 membered heterocyclic group" of this invention contains 1-3 heteroatoms; preferably, the "3-10 membered heterocyclic group" of this invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-10 membered heterocyclic group" of this invention contains 1-2 nitrogen atoms. Preferred groups include "3-8 membered heterocyclic group", "4-8 membered heterocyclic group", "5-8 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 "5-6 membered heterocyclic group". Specific examples include, but are not limited to: aziridine, 2H-aziridine, diaziridine, 3H-diazacyclopropenyl, aziridinebutyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, 1,3-dioxanepentyl, 1,4-dioxanehexadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrroleyl, pyrroleyl, imidazoyl, 4,5-dihydroimidazoyl, pyrazolyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazoyl, piperidinyl, 2-piperidinoneyl, piperazinyl, morpholinyl, 4,5-dihydrooxaneyl Azolyl, 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-one, 3,4-dihydro-2H-pyranyl, thiomorpholine-1,1-dioxide, tetrahydro-2H-thiopyran 1,1-dioxide, thiomorpholine-3-one 1,1-dioxide, dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide, 3,6-dihydro-2H-thiopyran 1,1-dioxide, 3-morpholinone, morpholine-3,5-Diketone, pyrrolidinylcyclopropyl, cyclopentylaziryl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzoimidazolyl, benzooxazolidinyl, benzothiazolyl, benzoisooxazolidinyl, benzoisothiazolyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzo[] Tetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrroleyl, pyridoimidazoyl, pyridooxazolyl, pyridothiazoyl, pyridoisooxazolyl, pyridoisothiazoyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrroleyl, pyrimidoimidazoyl, pyrimidooxazolyl, pyrimidothiazoyl, pyrimidoisooxazolyl pyrazolyl, pyrimidinositiazolyl, pyrimidinopiperidyl, pyrimidinomorpholinyl, pyrimidinopiperazinyl, pyrimidinotetrahydropyranyl, tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxacyclopentenyl, 2H-chromenyl, 2H-chromenyl-2-one, 4H-chromenyl, 4H-chromenyl-4-one, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furano[3,4-d] Imidazolyl, 3a,4,6,6a-tetrahydro-1H-furano[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothieno[c]imidazolyl, hexahydrofurano[c]imidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenten[c]pyrrolel, 4H-1,3-benzoxazinyl, etc.

[0182] The "6-10 aryl" group described in this invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl" and "8-10 membered fused-ring aryl". "6-8 membered monocyclic aryl" refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include, but are not limited to, phenyl, cyclooctatetraenyl, etc.; preferably phenyl. "8-10 membered fused-ring aryl" refers to an unsaturated, aromatic cyclic group containing 8-10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms, preferably "9-10 membered fused-ring aryl", specific examples include naphthyl, etc.

[0183] The "5-10-membered heteroaryl" as described in this invention refers to an aromatic cyclic group containing 5-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom), such as a 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, etc. It includes "5-8-membered mono-heteroaryl" and "8-10-membered fused heteroaryl". "5-8-membered mono-heteroaryl" refers to an aromatic monocyclic cyclic group containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom). Optionally, the ring atom (e.g., carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure can be oxidized. "5-8-membered mono-heteroaryl" includes, for example, "5-7-membered mono-heteroaryl", "5-6-membered mono-heteroaryl", "5-6-membered nitrogen-containing mono-heteroaryl", "5-membered nitrogen-containing mono-heteroaryl", etc. Specific examples of “5-8 membered monocyclic heteroaryl groups” include, but are not limited to, furanyl, thiopheneyl, 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-pyridonel, 4-pyridonel, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, aziridine-heptadienyl, 1,3-diazacyclicheptadienyl, aziridine-octatetraenyl, etc. "8-10 fused aryl" refers to an unsaturated aromatic cyclic structure consisting of 8-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen, oxygen, or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may be oxidized. This includes "9-10 fused heteroaryl", "8-9 fused heteroaryl", etc., whose fusion mode can be benzo5-6 heteroaryl, 5-6 heteroaryl and 5-6 heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanolothiophene, pyrazolooxazole, benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindolyl, benzooxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinoneyl, 4-quinolinoneyl, 1-isoquinolinoneyl, isoquinolinyl, acridineyl, phenanthridineyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthinyl, etc.

[0184] The phrase "optionally replaced by..." as described in this invention includes both "replaced" and "not replaced".

[0185] The "pharmaceutically acceptable salt" as described in this invention refers to the addition salt of pharmaceutically usable acids and bases, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, and salts formed with acidic or basic amino acids.

[0186] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester, particularly esters that are hydrolyzed in vivo and include esters that readily decompose in the human body, leaving behind a parent compound (the compound of general formula (I)) or its salt. The term "ester" as used in this invention may, for example, be selected from the following group: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (1) Alkoxy or amino substituted); (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valine or L-isoleucyl); and (4) mono-, di-, or triphosphate esters, etc.; (4) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (alkoxy or amino substitution).

[0187] The term "stereoisomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an alkene double bond, unless otherwise specified, they include cis and trans isomers. Compounds of this invention may exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are included within the scope of this invention. All enantiomers, diastereomers, racemic mixtures, mesomixes, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0188] The "therapeutic effective amount" as described in this invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that, when administered to a patient, at least alleviates the patient's symptoms. The actual amount comprising the "therapeutic effective amount" can vary depending on various factors, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.

[0189] Beneficial effects of the invention

[0190] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have excellent Menin inhibitory activity and can treat and / or prevent proliferative diseases, immune diseases and inflammatory diseases.

[0191] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0192] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good pharmacokinetic properties, longer duration of action and high bioavailability;

[0193] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0194] (5) The compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.

[0195] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be construed as the compounds provided in the embodiments of the present invention having only the following beneficial effects.

[0196] Experimental Example 1: In vitro cellular activity of the compounds of the present invention

[0197] Test samples: Some of the compounds of this invention, the chemical names and structures of which are given in the preparation examples.

[0198] Cell lines used in the experiment:

[0199] Experimental method for MIAPaCa-2: KRAS G12C mutant human pancreatic cancer cells and HCT116: KRAS G13D mutant human colon cancer cells (CelltiterGlo assay)

[0200] 1. Prepare cells

[0201] 1.1 Cell Culture:

[0202] All cells were adherent cells. MIAPaCa-2 cells were cultured in DMEM medium + 10% FBS + 1% PS + 2.5% horse serum, while HCT116 cells were cultured in McCoys 5A medium + 10% FBS + 1% PS. Cells were tested during the logarithmic growth phase.

[0203] 1.2 Preparation of cell suspension:

[0204] Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue rejection assay to ensure it was above 90%. The concentration was adjusted, and 90 μL of cell suspension was added to each well of a 96-well plate.

[0205] Table 1. Cell Seeding Number

[0206]

[0207] 2. Preparation of test compounds

[0208] 2.1 Preparation of stock solutions for test compounds

[0209] The test compound was prepared to 10 mM using DMSO as a test stock solution.

[0210] 2.2 Preparation of working solution for test compound

[0211] The test compound stock solution was 10 mM, serially diluted 3-fold to obtain 8 concentrations. Then, 2 μL of each serially diluted compound in DMSO was added to 198 μL of culture medium to prepare the working stock solution of the test compound (the compound concentration was 10 times the final concentration, with the highest concentration being 100 μM).

[0212] 2.3 Compound Treatment

[0213] Add 10 μL of the compound working stock solution (10-fold dilution, final DMSO concentration 0.1%) to each well of a 96-well plate seeded with cells.

[0214] The final concentrations of the tested compounds were: 10 μM, 3.33 μM, 1.11 μM, 370 nM, 123 nM, 41.1 nM, 13.7 nM, and 4.57 nM.

[0215] 2.4 Setting of reference holes

[0216] Solvent control: 0.1% DMSO;

[0217] Blank control: culture medium.

[0218] 2.5 Cultivation

[0219] The 96-well plate was placed in a 37°C, 5% CO2 cell culture incubator and cultured for 4 days.

[0220] 3. Testing

[0221] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes. Add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value using a multi-functional microplate reader.

[0222] 4. Data Processing

[0223] 1) Inhibition rate (%) = 1 - (test sample well reading - blank control well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0224] 2) Input the data into GraphPad Prism to plot the curve and obtain the IC. 50 .

[0225] Experimental Results and Conclusions

[0226] IC50 of the compound on the inhibitory activity of MIAPACA-2 and HCT116 cells 50 Values ​​less than 500nM are represented by +, 500nM-1000nM by ++, and 1000nM-5000nM by +++.

[0227] Table 2. In vitro cellular activities (IC50) of the compounds of the present invention 50 ,nM)

[0228]

[0229] As shown in Table 2, the compounds of the present invention can effectively inhibit the proliferation of MIAPACA-2 and HCT116 cells, indicating that the compounds of the present invention have the potential for clinical application in the treatment of cancer. Detailed Implementation

[0230] The technical solution of the present invention will now be described with reference to specific embodiments. These embodiments are merely some, not all, of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0231] The abbreviations used in the following experiments have the following meanings:

[0232] DIEA: N,N-Diisopropylethylamine

[0233] Example 1 Preparation of 1-((1R,5S,6s)-6-(4-(4-(1,1-thiomorpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-yl)prop-2-en-1-one (Compound 1)

[0234]

[0235] (1) Preparation of (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0236] At 20°C, (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (10 g, 47.4 mmol) was dissolved in methanol (200 ml), and potassium carbonate (19.6 g, 141.8 mmol) and (1-diazo-2-oxopropyl)phosphonate dimethyl ester (13.7 g, 58.5 mmol) were added. The reaction was carried out at 20°C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and column chromatography (SiO2, petroleum ether: ethyl acetate = 6:1) gave 6.2 g of product, with a yield of 63.2%.

[0237] (2) Preparation of (1R,5S,6S)-6-((4-hydroxyphenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0238] (1R,5S,6S)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (6.2 g, 29.9 mmol) was dissolved in triethylamine (100 mL), and p-iodophenol (7.2 g, 32.9 mmol), DPPF palladium dichloride (4.2 g, 6.0 mmol), and cuprous iodide (2.8 g, 15.0 mmol) were added. The reaction was carried out at 60 °C for 6 hours. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and column chromatography (SiO2, petroleum ether: ethyl acetate = 3:1) gave 5.3 g of product, yield 59.2%.

[0239] (3) Preparation of (1R,5S,6S)-6-(4-hydroxyphenylethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0240] At 20 °C, (1R,5S,6S)-6-((4-hydroxyphenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (5.3 g, 17.7 mmol) was dissolved in methanol (100 mL), and Pd / C (2.5 g) was added. The reaction was carried out at 20 °C for 12 hours. LC-MS showed that the reaction was complete. The mixture was filtered, and the filtrate was collected and evaporated to dryness to give 4.5 g, 83.8%.

[0241] (4) Preparation of (1R,5S,6S)-6-(4-(((trifluoromethyl)sulfonyl)oxy)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0242] At 20 °C, (1R,5S,6S)-6-(4-hydroxyphenylethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (4.5 g, 14.6 mmol) was dissolved in acetonitrile (100 mL), and DIEA (5.7 g, 44.4 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (5.5 g, 15.4 mmol) were added. The reaction was carried out at 20 °C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1) gave 5.4 g of product, with a yield of 83.9%.

[0243] (5) Preparation of (1R,5S,6s)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester: (1R,5S,6s)-6-(4-(((trifluoromethyl)sulfonyl)oxy)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.1 g, 2.5 mmol) was dissolved in 1,4-dioxane (100 mL), and pinacol diborate (887 mg, 3.5 mmol), DPPF palladium dichloride (337 mg, 0.46 mmol), and potassium acetate (677 mg, 6.9 mmol) were added. The reaction was carried out at 100 °C for 12 hours. LC-MS showed that the reaction was complete. No further processing was performed, and the product was directly used in the next step of the reaction.

[0244] (6) Preparation of (1R,5S,6s)-6-(4-(4-(1,1-thiomorpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0245] Add 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (794 mg, 2.1 mmol), DPPF palladium dichloride (154 mg, 0.21 mmol), sodium carbonate (1.1 g, 10.5 mmol), and water (5 mL) to the reaction solution obtained in the previous step. The reaction was carried out at 100 °C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and column chromatography (SiO2, dichloromethane:methanol = 20:1) yielded 185 mg, with a two-step yield of 13.6%.

[0246] (7) Preparation of 1,1-dioxide of 4-(6-(4-(2-((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine

[0247] A solution of (1R,5S,6s)-6-(4-(4-(1,1-thiomorpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (50 mg, 0.093 mmol) in methanol (10 mL) was added to a solution of hydrogen chloride-dioxane (10 mL). The reaction was carried out at 20 °C for 30 minutes. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness to obtain 55 mg of crude product, which was directly used in the next step of the reaction.

[0248] (8) Preparation of 1-((1R,5S,6s)-6-(4-(4-(1,1-thiomorpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-yl)prop-2-en-1-one

[0249] 4-(6-(4-(2-((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (60 mg, crude) was dissolved in DMF (10 mL), and DIEA (55 mg, 0.43 mmol) and acryloyl chloride (11 mg, 0.13 mmol) were added. The reaction was carried out at -10 °C for 30 min. LC-MS showed that the reaction was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was evaporated to dryness. A plate (SiO2, dichloromethane:methanol = 10:1) was prepared to give 21 mg. The two-step yield was 46%.

[0250] Molecular formula: C 26 H 29 N5O3S molecular weight: 491.6 LC-MS (m / z): 492.2 (M+H) + )

[0251] 1 H-NMR(400MHz,DMSO-d6)δ:12.29(s,1H),8.24(s,1H),7.82-7.79(d,J=8 .1,2H),7.28-7.26(d,J=7.8,2H),7.09(s,1H),6.30-6.25(m,1H),6.09- 6.04(m,1H),5.64-5.62(m,1H),4.34-4.31(m,4H),3.86-3.81(m,3H),3. 57-3.34(m,4H),2.75-2.71(m,2H),1.69-1.13(m,5H),0.73-0.64(m,1H).

[0252] Example 2 Preparation of 1-((1R,5S,6S)-6-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one (Compound 2)

[0253]

[0254] Preparation of (1R,5S,6s)-6-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0255] To the reaction solution of (1R,5S,6s)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15 mL, 1.8 mmol), 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.8 mmol), DPPF-palladium dichloride (263 mg, 0.36 mmol), sodium carbonate (572 mg, 5.4 mmol), and water (6 mL) were added. The reaction was carried out at 100 °C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness, and column chromatography (SiO2, dichloromethane:methanol = 20:1) yielded 256 mg, with a yield of 32.5%.

[0256] (2) Preparation of (1R,5S,6s)-6-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0257] (1R,5S,6S)-6-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (256 mg, 0.58 mmol) was dissolved in 1,4-dioxane (30 mL), followed by (3,5-difluorophenyl)boric acid (132 mg, 0.84 mmol), DPPF-palladium dichloride (84 mg, 0.12 mmol), sodium carbonate (184 mg, 1.7 mmol), and water (5 mL). The reaction was carried out at 100 °C for 12 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness, and column chromatography (SiO2, n-heptane:ethyl acetate = 0:1) yielded 50 mg of the product, with a yield of 16.6%.

[0258] (3) Preparation of 6-(4-(2-((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0259] To (1R,5S,6s)-6-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (50 mg, 0.097 mmol), a hydrogen chloride-dioxane solution (4 M, 10 mL) was added. The reaction was carried out at 25 °C for 30 minutes. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness to give 60 mg of crude product, which was directly used in the next step of the reaction.

[0260] (4) Preparation of 1-((1R,5S,6s)-6-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-3-azabicyclo[3.1.0]hexane-3-yl)prop-2-en-1-one

[0261] 6-(4-(2-((1R,5S,6S)-3-azabicyclo[3.1.0]hexane-6-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, crude) was dissolved in DMF (10 mL), and DIEA (39 mg, 0.30 mmol) and acryloyl chloride (9.0 mg, 0.10 mmol) were added. The reaction was carried out at 25 °C for 30 min. LC-MS showed that the reaction was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was evaporated to dryness. A plate (SiO2, dichloromethane:methanol = 10:1) was prepared to give 42 mg. The two-step yield was 92.1%. Molecular formula: C 28 H 24 F2N4O molecular weight: 470.5 LC-MS (m / z): 471.2 (M+H) + )

[0262] 1 H-NMR(400MHz,DMSO-d6)δ:12.85(s,1H),8.84(s,1H),8.10-8.00(m,2H),7.99-7.90(m,2H),7.60-7.45(m,2H),7.45-7.35(m,2H),6.55-6.40 (m,1H),6.12-6.04(m,1H),5.75-5.62(m,1H),3.72-3.55(m,3H),2.81 -2.75(m,2H),1.75-1.45(m,2H),1.45-1.30(m,3H),0.50-0.40(m,1H).

[0263] The compounds shown in the following table were prepared using the same or similar methods as those used in the above examples:

[0264]

[0265] The Menin inhibitor and its applications provided by this invention have been described in detail above. Specific embodiments have been used to illustrate the principles and implementation methods of this invention. These embodiments are merely illustrative and are intended to aid in understanding the method of this invention. It should be noted that those skilled in the art can make various improvements and modifications to this invention without departing from its principles, and these improvements and modifications also fall under the protection of the claims of this invention.

Claims

1. A compound of general formula (I), its pharmaceutically acceptable salt, ester, or stereoisomer thereof, in, Z1, Z2, Z3, and Z4 are each independently selected from CR a Or N; X1, X2, and X4 are each independently selected from N or CR. a ; X3 is selected from S, O, NR c or CR a R b ; X5 is selected from N or CR2; Y1 is selected from CH or N; Y2 is selected from O and CR. a1 R b1 or NR c1 ; Y3 is selected from CR a3 Or N; Y4 is selected from CR a4 Or N; Y5 is selected from CR a5 R b5 C(O), S(O)2, O, S or NR c5 ; Y6 is selected from CR a6 R b6 C(O), S(O)2, O, S or NR c6 ; Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R)-. c2 )-、-C(R a2 (R) b2 )-; R a1 R b1 Each is independently selected from hydrogen, cyano, halogen, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -C(R a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ), -N(R c3 )-S(O)2-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-S(O)2-C(R a3 )=C(R a3 (R) b3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), -S(O)-C(R) a3 )=C(R a3 (R) b3 ), -OC(R a3 (R) b3 )-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(R a3 (R) b3 )-C(R a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl groups are optionally surrounded by one or more halogens, cyano groups, or C groups. 1-6 Alkyl substitution; Each R c Each R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and 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, -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C≡C(R) a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Each R1, R2, each R3, each R a Each R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, -C(O)-NH2, C 1-6 alkyl carbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl; m and q are independent integers from 0 to 4; n is an integer between 1 and 4.

2. The compound of claim 1, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, having the structure shown in formula (II), in, X1, X2, and X4 are each independently selected from N or CR. a ; X3 is selected from S, O, NR c or CR a R b ; Y1 is selected from CH or N; Y2 is selected from O and CR. a1 R b1 or NR c1 ; Y3 is selected from CR a3 ; Y4 is selected from CR a4 ; Y5 is selected from CR a5 R b5 or NR c5 ; Y6 is selected from CR a6 R b6 or NR c6 ; Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclic, 6-10 membered aryl, and 5-8 membered heteroaryl; Each L is independently selected from -C(O)- and -N(R)-. c2 )-、-C(R a2 (R) b2 )-、-S(O)2-; R a1 R b1 Each is independently selected from hydrogen, cyano, halogen, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -C(R a3 (R) b3 )-N(R C3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-3 halogen, cyano, or C groups. 1-6 Alkyl substitution; R c R c1 Each R c2 Each R c3 Each R c4 R c5 R c6 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C≡C(R) a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are optionally substituted by 1-3 substituents, wherein each substituent is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; m and q are independent integers from 0 to 4; n is an integer between 1 and 4.

3. The compound of claim 1 or 2, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, having the structure shown in formula (III): in, X3 is selected from NR c or CR a R b ; Y1 is selected from CH or N; Y2 is selected from CR a1 R b1 or NR c1 ; Y3 is selected from CR a3 ; Y4 is selected from CR a4 ; Y5 is selected from CR a5 R b5 ; Y6 is selected from CR a6 R b6 ; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; Each L is selected independently -C(R) a2 (R) b2 )-; R a1 R b1 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, -C(R) a3 (R) b3 )-N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-C(R a3 )=C(R a3 (R) b3 -C(O)-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 ), -N(R c3 )-C(O)-R a3 -N(R) c3 (R) c4 ); the aforementioned C 1-6 Alkyl groups are optionally surrounded by 1-2 halogen, cyano, or C groups. 1-6 Alkyl substitution; R c R c1 Each R c3 Each R c4 Each is independently selected from hydrogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C(O)-R a3 -C(O)-C(R) a2 (R) b2 )-R a3 -C(O)-C(R) a3 )=C(R a3 (R) b3 -C(O)-C≡C(R) a3 -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-6 Alkyl, C 1-6 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Each R1, R2, each R3, each R a R b Each R a2 Each R b2 Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonamide; m and q are independent integers from 0 to 3; n is an integer between 1 and 3.

4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, having the structure shown in formula (IV), Ring A is selected from 5-6 membered heterocyclic groups, phenyl groups, or 5-6 membered heteroaryl groups; R c R c1 Each is independently selected from hydrogen, cyano, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, -C(O)-R a3 -C(O)-CH2-R a3 -C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -S(O)2-R a3 -S(O)2-C(R) a3 )=C(R a3 (R) b3 ), the C 1-4 Alkyl, C 1-4 The alkoxy group may optionally be substituted by 1-3 substituents, each substituent being independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C... 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy; Each R1, R2, each R3, R a Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, and 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, C 1-4 alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonamide; m and q are independently 0, 1, and 2, respectively.

5. The compound of claim 4, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein, Ring A is selected from piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanehexyl, 1,3-dioxanehexyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridineyl, pyridazinyl, pyrroleyl, pyrazolyl, imidazolyl, etc. Each R1, R2, each R3, R a Each R a3 Each R b3 R a4 R a5 R b5 R a6 R b6 Each group is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. R c R c1 Each of the following groups is independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, and -C(O). -CH2-CN, -C(O)-CH(CH3)-CN, -CH2-CN, -CH(CH3)-CN, -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C (O)-C(Cl)=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3.

6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, ester, or stereoisomer thereof, having the structure shown in general formula (IX), Each R1, R2, each R3, R a R c R c1 The definitions of m and q are as described in any one of claims 1-5.

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

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

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

10. Use of the compound of any one of claims 1-7, its pharmaceutically acceptable salt, ester or stereoisomer, or the pharmaceutical preparation of claim 8, or the pharmaceutical composition of claim 9 in the preparation of a medicament for the treatment and / or prevention of proliferative diseases, immune diseases, or inflammatory diseases.

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