Condensed ring compound and use thereof

Abstract

The invention relates to the technical field of medicines, in particular to a fused ring 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 proliferative diseases, immune diseases and inflammatory diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to condensed ring compounds, 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 drugs for treating and / or preventing proliferative diseases, immune diseases and inflammatory diseases. Background Art

[0002] Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 at the tail of histone H3 in important regulatory regions of the genome, thereby playing a key role by 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 is located on chromosome 11q23 and is very prone to rearrangement. More than 80 genes have been found to form gene fusions with MLL, including AF4, AF9, AF10, ENL, AF6 and ELL. MLL gene rearrangement occurs in about 5% of acute lymphoblastic leukemia (ALL), about 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 biphenotypic) leukemia (MLL) cases. MLL rearrangement is a strong predictor of poor prognosis for leukemia patients. Existing treatments have low efficacy and a 5-year overall survival rate of 10-35%.

[0004] Menin is the expression product of the Multiple Endocrine Neoplasia 1 (MEN1) gene. It exists in the cell nucleus and, as a scaffold protein, plays a variety of key 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 to be a key oncogenic cofactor of MLL and is involved in regulating the proliferation and differentiation of tumor cells. When the MLL gene undergoes a translocation rearrangement mutation, the corresponding MLL fusion protein is expressed in the cell, which interacts with the Menin protein and activates its downstream genes, such as HOX (homeotic gene) and MEIS1 (mixed lineage leukemia oncogene), promoting the occurrence of leukemia. In pancreatic islet cells, Menin mutations will lead to excessive proliferation of β cells and the production of pancreatic β cell tumors. Excessive Menin expression levels can lead to the obstruction of β cell proliferation, resulting in relatively insufficient insulin secretion, which in turn promotes diabetes.

[0005] Nucleophosmin 1 (NPM1) and nucleoporin 98 (NUP98) also rely on the interaction between Menin and MLL to cause leukemia, which is associated with the upregulation of HOXA and MEIS1. NPM1 mutation is the most common genetic alteration in adult AML, accounting for about 20%-30%. The frequency of NUP98 rearrangement in adult AML patients is very low (about 1%-2%), but the frequency of NUP8 rearrangement in patients with 11p15 abnormalities is 35%. The frequency of NUP98 rearrangement in childhood AML is higher, with 6% to 10% of cases having this translocation.

[0006] MYC is a transcription factor associated with tumorigenesis, which usually regulates genes related to cell proliferation, differentiation and apoptosis. Abnormal expression of MYC can be caused by a variety of factors, including the activation of RAS. Its activity depends largely on its interaction with Menin. It is abnormally expressed in many tumors such as DLBCL, MM and KRAS-mutated solid tumors (colon cancer, pancreatic cancer and lung cancer), and plays a key role in the occurrence and development of tumors.

[0007] Therefore, inhibiting the interaction between Menin and MLL or inhibiting the effect of Menin on MYC or KRAS will become an effective treatment for hematological tumors, lymphomas and solid tumors. However, the effectiveness of the compounds currently under development is limited, and there is an urgent need to develop compounds with strong inhibitory effects, broad action ranges and novel structures. Summary of the invention

[0008] The object of the present invention is to provide a condensed ring compound and its application. The specific technical scheme is as follows:

[0009] In certain embodiments, the present invention first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof:

[0010]

[0011] in,

[0012] X1, X2, X4, Z2, and Z3 are independently selected from N or CR a ;

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

[0014] Y1 and Z1 are independently selected from CH or N;

[0015] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0016] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0017] Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R c2 )-or-C(R a2 )(R b2 )-;

[0018] R a1 , R b1 are independently selected from hydrogen, cyano, halogen, 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)-Ra3 、-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 The alkyl group is optionally substituted with one or more halogen, cyano or C 1-6 Alkyl substitution;

[0019] R c , R c1 , each R c3 , R c4 are independently selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-C≡C(R a3)、S(O)2-C(R a3 )=C(R a3 )(R b3 )、-S(O)2-R a3 , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0020] Each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, 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;

[0021] m and q are each independently an integer from 0 to 4;

[0022] n1 and n2 are each independently an integer from 0 to 3;

[0023] n, n3, and n4 are each independently an integer of 1-4.

[0024] In certain embodiments, X1 and X2 are independently selected from N; X3 is selected from O, NR c or CR a R b ;

[0025] X4 Selected from CR a .

[0026] In certain embodiments, X1 and X2 are independently selected from N; X3 is selected from NR c ; X4 selected from CR a .

[0027] In certain embodiments, Y1 is selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 .

[0028] In certain embodiments, Y1 is selected from CH; Y2 is selected from NR c1 .

[0029] In certain embodiments, Z1 and Z2 are each independently selected from N.

[0030] In certain embodiments, Z3 is selected from N.

[0031] In certain embodiments, Z3 is selected from CR a .

[0032] In certain embodiments, Z3 is selected from CH.

[0033] In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl, or 5-8 membered heteroaryl.

[0034] In certain embodiments, Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0035] In certain embodiments, Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl.

[0036] In certain embodiments, Ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl.

[0037] In certain embodiments, Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, tetrahydropyranyl.

[0038] In certain embodiments, each L is independently selected from -O-, -N(R c2 )-or-C(R a2 )(R b2 )-.

[0039] In certain embodiments, each L is independently -C(R a2 )(Rb2 )-.

[0040] In certain embodiments, each L is independently -CH2-.

[0041] In certain embodiments, R a1 , R b1 are independently selected from hydrogen, cyano, halogen, 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 a2 、-C(O)-C(R a3 )=C(R a3 )(R b3 )、-N(R c3 )-C(O)-R a2 、-N(R c3 )(R c4 ); said C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen, cyano or C 1-6 Alkyl substitution.

[0042] In certain embodiments, R a1 , R b1 are independently selected from hydrogen, cyano, 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 a2 、-C(O)-C(R a3 )=C(R a3 )(R b3)、-N(R c3 )-C(O)-R a2 、-N(R c3 )(R c4 ); said C 1-4 The alkyl group is optionally substituted with 1-2 halogen, cyano or C 1-4 Alkyl substitution.

[0043] In certain embodiments, R a1 , R b1 are independently selected from hydrogen, cyano, -C(R 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)-C 1-4 Alkoxy, -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 ).

[0044] In certain embodiments, R a1 , R b1 They 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)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -N(H)-C(O)-CH3, -N(H)-C(O)-CH2CH3, -N(CH3)-C(O)-CH2CH3, -N(H)-C(O)-H, -N(CH3)-C(O)-CH3, -N(H)-CN, -N(CH3)-CN.

[0045] In certain embodiments, each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl.

[0046] In certain embodiments, each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0047] In certain embodiments, each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2 Each 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, and trifluoromethoxy.

[0048] In certain embodiments, R c , each R c1 , each R c3 , R c4 are independently 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 a2 、-C(O)-C(R a3 )=C(Ra3 )(R b3 )、-C(O)-C≡C(R a3 )、-S(O)2-R a2 、S(O)2-C(R a3 )=C(R a3 )(R b3 ), 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0049] In certain embodiments, R c , each R c1 , each R c3 , R c4 are independently selected from hydrogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-C 1-4 Alkoxy, C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-C 1-4 Alkyl, -S(O)2-CH=CH2, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0050] In certain embodiments, R c , R c1 , each R c3 , R c4 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)-C 1-4 Alkyl, -C(O)-C 1-4 Alkoxy, -C(O)-H, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-C 1-4 Alkyl, -S(O)2-CH=CH2, 5-6 membered heteroaryl, 5-6 membered heterocyclic group.

[0051] In certain embodiments, R c , R c1 , each R c3 , R c4are 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)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡ C(CH3), -C(O)-NH2, -S(O)2-CH3, -S(O)2-CH=CH2, 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl.

[0052] In certain embodiments, R c , R c1 , each R c3 , R c4 They are independently selected from hydrogen, cyano, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

[0053] In certain embodiments, m and q are each independently an integer from 0 to 3;

[0054] n1 and n2 are each independently an integer from 0 to 2;

[0055] n, n3, and n4 are each independently an integer of 1-3.

[0056] In certain embodiments, m and q are independently 0, 1, or 2;

[0057] n1 and n2 are independently 0, 1, and 2;

[0058] n is 1, 2 or 3;

[0059] n3 and n4 are independently 1 and 2, respectively.

[0060] In certain embodiments,

[0061] Select from the following structures:

[0062]

[0063] Each R2, R a , each R c The definition of is as described in any of the above technical solutions.

[0064] In certain embodiments,

[0065] Select from the following structures:

[0066]

[0067] Each R a1 , each R b1 , each R c1 The definition of 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, ester or stereoisomer thereof, wherein,

[0069] X1 and X2 are independently selected from N;

[0070] X3 is selected from O, NR c or CR a R b ;

[0071] X4 Selected from CR a ;

[0072] Z2 and Z3 are independently selected from N or CR a ;

[0073] Y1 and Z1 are independently selected from CH or N;

[0074] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0075] Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl or 5-8 membered heteroaryl;

[0076] Each L is independently selected from -O-, -N(R c2 )-or-C(R a2 )(R b2 )-;

[0077] R a1 , R b1 are independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, -C(Ra3 )(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 C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen, cyano or C 1-6 Alkyl substitution;

[0078] R c , R c1 , each R c3 , R c4 are independently 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)-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 ), 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0079] Each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3, each R c2 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl;

[0080] m and q are each independently an integer from 0 to 3;

[0081] n1 and n2 are each independently an integer from 0 to 2;

[0082] n, n3, and n4 are each independently an integer of 1-3.

[0083] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0084] Select from the following structures:

[0085]

[0086] Y1 and Z1 are independently selected from CH or N;

[0087] Y2 is selected from CR a1 R b1 or NR c1 ;

[0088] Z2 and Z3 are independently selected from N or CR a ;

[0089] Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl;

[0090] Each L is independently -C(R a2 )(R b2 )-;

[0091] R a1 , R b1 are independently selected from hydrogen, cyano, 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 ); said C 1-4 The alkyl group is optionally substituted with 1-2 halogen, cyano or C 1-4 Alkyl substitution;

[0092] Each R1, each R2, each R3, R a , each R a2 , each R a3 , each R b2 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy;

[0093] R c , R c1 , each R c3 , R c4 are independently selected from hydrogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-C 1-4 Alkoxy, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-C 1-4 Alkyl, -S(O)2-CH=CH2, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0094] m and q are independently 0, 1, and 2;

[0095] n1 and n2 are independently 0, 1, and 2;

[0096] n is 1, 2 or 3;

[0097] n3 and n4 are independently 1 and 2, respectively.

[0098] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, has a structure shown in the following formula (II):

[0099]

[0100] Among them, ring A, Y1, Y2, each R1, R2, each R3, R a , R a1 , R a3 , R b1 , R b3 , R c , R c1 , R c3 , R c4 , n1, n2, n3, n4, m, q are defined as described in any of the preceding schemes.

[0101] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, has a structure shown in the following formula (III):

[0102]

[0103] Among them, Y1, Y2, each R1, R2, each R3, R a , R a1 , R b1 , each R a3 , each R b3 , R c , R c1 , each R c3 , R c4 , n1, n2, n3, n4, m, q are defined as described in any of the preceding schemes.

[0104] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, has a structure shown in the following formula (IV):

[0105]

[0106] Among them, R2, each R1, each R3, R a , R a1 , each R a3 , R b1 , each R b3 , R c , R c1 , each R c3 , each R c4 , n1, n2, n3, n4, and m are defined as described in any of the preceding schemes.

[0107] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, has a structure shown in the following formula (V):

[0108]

[0109] Among them, R c1 , n1, n2, n3, and n4 are defined as described in any of the aforementioned schemes.

[0110] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0111] Ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl;

[0112] Each L is independently -C(R a2 )(R b2 )-;

[0113] R a1 , R b1 are independently selected from hydrogen, cyano, -C(R 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 Alkoxy;

[0114] Each R1, R2, each R3, R a , R b , each R a2 , each R a3, each R b2 , each R b3 Each of the following is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0115] R c , R c1 , each R c3 , R c4 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)-CH=CH2, -C(O)-C≡CH, -C(O)-C ≡C-CH3, -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl.

[0116] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0117] Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, tetrahydropyranyl;

[0118] Select from the following structures:

[0119]

[0120] Each R a1 , each R b1Each of the following groups is 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)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -N(H)-C(O)-CH3, -N(H)-C(O)-CH2CH3, -N(CH3)-C(O)-CH2CH3, -N(H)-C(O)-H, -N(CH3)-C(O)-CH3, -N(H)-CN, -N(CH3)-CN;

[0121] Each R c1 They are independently selected from hydrogen, cyano, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

[0122] In certain embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof,

[0123] wherein ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxane, 1,3-dioxane, tetrahydropyranyl;

[0124] Select from the following structures:

[0125]

[0126] Each R a1 , each R b1 are independently selected from hydrogen, cyano, 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)-Ra2 、-C(O)-C(R a3 )=C(R a3 )(R b3 )、-N(R c3 )-C(O)-R a2 、-N(R c3 )(R c4 ), the C 1-4 The alkyl group is optionally substituted with 1-2 halogen, cyano or C 1-4 Alkyl substitution;

[0127] R c , each R c1 , each R c3 , R c4 are independently 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 a2 、-C(O)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-C≡C(R a3 )、-S(O)2-R a2 、-S(O)2-C(R a3 )=C(R a3 )(R b3 ), 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0128] Each R1, R2, each R3, each R a , R b , each R a3 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy;

[0129] m and q are independently 0 and 1, respectively.

[0130] In some embodiments of the present invention, the structure of the provided compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof is as follows:

[0131]

[0132] The present invention also provides a pharmaceutical composition comprising a compound represented by the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), 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.

[0133] The second therapeutic agent described in the present 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.

[0134] The present invention also provides a pharmaceutical preparation, which contains the compounds represented by the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), their pharmaceutically acceptable salts, esters or stereoisomers, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is in any dosage form that is clinically or pharmaceutically acceptable.

[0135] In some embodiments of the present invention, the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or pulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, adhesives, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives can be omitted or appropriate additives can be added according to the properties of the drugs. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition can be made into inhalants or sprays, etc.

[0136] The pharmaceutical carrier and / or diluent available in the pharmaceutical composition of the present invention or the pharmaceutical preparation can be any conventional carrier and / or diluent in the pharmaceutical preparation field, and the selection of specific carrier and / or diluent will depend on the mode of administration or disease type and state for treating a specific patient. The preparation method of the suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of the pharmaceutical field technician. For example, the pharmaceutical carrier and / or diluent can include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. in the pharmaceutical composition. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0137] The present invention also provides the use of compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), 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 proliferative diseases, immune diseases, and inflammatory diseases.

[0138] The present invention also provides a method for treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), 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.

[0139] The proliferative disease is selected from cancer or benign tumors, including but not limited to blood tumors, colorectal cancer, gastric cancer, ovarian cancer, breast cancer, endometrial cancer, cervical cancer, cervical squamous cell carcinoma, endocervical 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 blood tumor includes but is not limited to leukemia, multiple myeloma, and malignant lymphoma; the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer; the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, and meningioma.

[0140] In the specification and claims of the present application, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structural formula shall prevail.

[0141] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

[0142] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0143] The term "halogenated" as used herein means that any hydrogen in the substituent may be replaced by one or more halogens which may be the same or different. "Halogen" is as defined above.

[0144] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-5 Alkyl", "C 1-4 Alkyl", "C 1-3 Alkyl", "C 1-2 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 2-4 Alkyl", "C 2-3 Alkyl", "C 3-6 Alkyl", "C 3-5 Alkyl", "C 3-4 Alkyl", "C 4-6 Alkyl", "C 4-5 Alkyl", "C 5-6 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The “C 1-4 "Alkyl" refers to C 1-6 Specific examples of alkyl groups contain 1 to 4 carbon atoms.

[0145] The "C 2-6 "Alkenyl" refers to a linear or 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- ...1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2-propenyl, 1-ethyl-2- -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.

[0146] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms and 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.

[0147] 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 The group formed by alkyl-OC(O)-, wherein "C 1-6 "Alkyl" is as defined above.

[0148] The “C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Alkyl aminoacyl, C 1-4 Alkyl amido, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylcarbonyl, C 1-4 "Alkoxycarbonyl" refers to a C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 Alkyl)2-N-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-C(O)-NH-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S(O)2-NH-, C 1-4 Alkyl-NH-S(O)2-, C 1-4 Alkyl-C(O)-, C 1-4 The group formed by alkyl-OC(O)-, wherein "C 1-4 "Alkyl" is as defined above.

[0149] The "halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, halogenated C 1-6 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, carboxyl groups, etc., which are substituted by C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by the hydrogen atoms in an alkoxy group.

[0150] 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, etc., which are substituted by C 1-4 Alkyl, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0151] The "3-10 membered cycloalkyl group" described in the present invention refers to a saturated or partially saturated non-aromatic cyclic alkyl group containing 3-10 carbon atoms, including "monocyclic alkyl groups" and "condensed cyclic alkyl groups".

[0152] The "monocycloalkyl" described in the present invention refers to a saturated or partially saturated monocyclic alkyl group that is not aromatic, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl", "6-7 membered cycloalkyl", "6-8 membered cycloalkyl", "7-8 membered cycloalkyl", "3-6 membered saturated cycloalkyl", "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, cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentanyl (cyclopentyl), cyclohexanyl (cyclohexyl), cycloheptanyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-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.

[0153] The "condensed cycloalkyl" described 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 an aromatic ring, but the condensed ring as a whole does not have aromaticity; the condensed form may be: 5-6-membered cycloalkyl and 5-6-membered cycloalkyl, benzo 5-6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl, etc. Examples include, but are not limited to: bicyclo[3.1.0]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.

[0154] The "3-10 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic or condensed ring group containing at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and 3-10 ring atoms, and having no aromaticity, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure may be oxidized. The "3-10 membered heterocyclic group" of the present invention includes a "3-10 membered saturated heterocyclic group" and a "3-10 membered partially saturated heterocyclic group". Preferably, the "3-10 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-10 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 "3-10 membered heterocyclic group" of the present invention contains 1-2 nitrogen atoms. The “3-10 membered heterocyclic group” is preferably a “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 the “3- to 10-membered heterocyclic group” include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, 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, benzooxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl yl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridotisoxazolidinyl, pyridothiazolidinyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidotisoxazolidinyl, pyrimidothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3 ]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl, 4,6-dihydro-1H- Thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, and the like.

[0155] 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 group" and "8-10 membered condensed ring aryl group".

[0156] 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.

[0157] 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, preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl and the like.

[0158] The "5-10 membered heteroaryl" of the present 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, an oxygen atom or a sulfur atom), for example, a 5-10 membered nitrogen-containing heteroaryl, a 5-10 membered oxygen-containing heteroaryl, a 5-10 membered sulfur-containing heteroaryl, etc. It includes "5-8 membered single heteroaryl" and "8-10 membered condensed heteroaryl".

[0159] The "5-8-membered single heteroaryl" of the present invention refers to a monocyclic cyclic group with aromaticity 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 can be oxo-substituted. "5-8-membered single heteroaryl" includes, for example, "5-7-membered single heteroaryl", "5-6-membered single heteroaryl", "5-6-membered nitrogen-containing single heteroaryl", "5-membered nitrogen-containing single heteroaryl" and the like. Specific examples of “5-8 membered monocyclic heteroaryl” include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 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.

[0160] The "8-10 membered fused heteroaryl" described in the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms, 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). Optionally, the ring atoms (such as 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-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0161] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0162] The "pharmaceutically acceptable salt" described in the present invention refers to pharmaceutically acceptable acid and base addition salts, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, salts formed with acidic amino acids or basic amino acids, etc.

[0163] The "ester" of the present invention refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes an ester that is easily decomposed in the human body to leave the parent compound (the compound of general formula (I)) or its salt. The "ester" of the present invention can be selected from the following groups: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl part of the carboxylic acid compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight or branched alkyl, C 1-6 Straight-chain or branched alkyl (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g. methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g. benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C 6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4(2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); and (4) mono-, di- or triphosphates, etc.; (5) esters obtained by esterification with alcohol compounds, wherein the non-hydroxyl portion of the alcohol compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight or branched alkyl, C 1-6 Straight-chain or branched alkyl (e.g., methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g. methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g. benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g. phenoxymethyl), C 6-10 Aryl (e.g. phenyl, optionally substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0164] The "stereoisomer" of the present invention refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, unless otherwise specified, cis isomers and trans isomers are included. The compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included in the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds are included in the scope of the present invention.

[0165] The "therapeutically effective amount" of the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least alleviate the symptoms of the patient's condition when administered to the patient. The actual amount comprising the "therapeutically effective amount" will vary depending on a variety of circumstances, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.

[0166] Advantageous Effects of the Invention

[0167] (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;

[0168] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0169] (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;

[0170] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0171] (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.

[0172] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be understood as the compounds provided in the embodiments of the present invention only having the following beneficial effects.

[0173] Experimental Example 1 In vitro cytological activity of the compounds of the present invention

[0174] Test product

[0175] 1. For some compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0176] 2. Reagents and cell lines used in the experiment:

[0177] MIA PaCa-2: KRAS G12C mutant human pancreatic cancer cells

[0178] HCT116: KRAS G13D mutant human colon cancer cells

[0179] Experimental method (CelltiterGlo assay)

[0180] 1. Cell Preparation

[0181] 1.1 Cell culture:

[0182] All cells were adherent cells, the culture medium of MIA PaCa-2 cells was DMEM medium + 10% FBS + 1% PS + 2.5% horse serum, and the culture medium of HCT116 cells was McCoys 5A medium + 10% FBS + 1% PS. The cells were tested in the logarithmic growth phase.

[0183] 1.2 Preparation of cell suspension:

[0184] Harvest cells in the logarithmic growth phase and count them using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust to an appropriate concentration and add 90 μL of the cell suspension to each 96-well plate.

[0185] Table 1. Cell seeding number

[0186]

[0187] 2. Preparation of test compounds

[0188] 2.1 Preparation of test compound stock solution

[0189] Test compounds were prepared in DMSO to 10 mM as assay stock solutions.

[0190] 2.2 Preparation of test compound working solution

[0191] The test compound stock solution was 10 mM, and was diluted 3 times in series, with a total of 8 concentrations. Then, 2 μL of the DMSO-diluted compound was added to 198 μL of culture medium to form the test compound working stock solution (the compound concentration was 10 times the final concentration, and the highest concentration was 100 μM).

[0192] 2.3 Compound treatment

[0193] 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.

[0194] The final concentrations of the tested compounds were: 10 μM, 3.33 μM, 1.11 μM, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.57 nM.

[0195] 2.4 Control well setting

[0196] Solvent control: 0.1% DMSO;

[0197] Blank control: culture medium.

[0198] 2.5 Cultivation

[0199] The 96-well plate was placed in a 37°C, 5% CO2 cell culture incubator and cultured for 4 days.

[0200] 3. Detection

[0201] Melt the CTG reagent and equilibrate the 96-well plate to room temperature for 30 minutes, add 60 μL of reagent (Celltiter Gloassay kit) to each well, shake on an oscillator for 2 minutes to mix (protect from light), and incubate at room temperature for 20 minutes (protect from light). Read the light signal value with a multifunctional microplate reader.

[0202] 4. Data Processing

[0203] 1) Inhibition rate (%) = 1-(test well reading-blank control well reading) / (DMSO solvent control well reading-blank control well reading) × 100%;

[0204] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0205] Experimental results and conclusions

[0206] IC of the inhibitory activity of the compounds on MIA PACA-2 cells and HCT116 cells 50 Values ​​less than 100 nM are indicated by +, 100 nM-1000 nM are indicated by ++, and 1000 nM-3000 nM are indicated by +++.

[0207] Table 2. In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0208]

[0209] As shown in Table 2, the compounds of the present invention can effectively inhibit the proliferation of MIA PACA-2 and HCT116 cells, indicating that the compounds of the present invention have clinical application potential in treating cancerous diseases. DETAILED DESCRIPTION

[0210] The technical solution of the present invention will be described below in conjunction with specific embodiments, and the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0211] The abbreviations used in the following experiments have the following meanings:

[0212] DCM: dichloromethane;

[0213] EA: ethyl acetate;

[0214] TEA: triethylamine;

[0215] DMF: N,N-dimethylformamide.

[0216] Example 1 Preparation of 1-(7-((5-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 1)

[0217]

[0218] (1) Preparation of 4-(6-(1H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0219] At 20°C, 4-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (2.0 g, 4.3 mmol) was dissolved in dioxane (40 ml) and H2O (10 ml), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.6 g, 6.5 mmol), Pd(dppf)Cl2 (302 mg, 0.43 mmol) and K2CO3 (1.8 g, 12.9 mmol) were added. The reaction was carried out at 100°C for 7 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and purified by column chromatography (SiO2, petroleum ether:ethyl acetate=1:1) to obtain 700 mg of the product. The yield was 36.2%.

[0220] (2) Preparation of tert-butyl 7-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0221]

[0222] At 20°C, tert-butyl 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 2.0 mmol) was dissolved in DCM (20 ml), and triethylamine (606 mg, 6.0 mmol) and methylsulfonyl chloride (344 mg, 3.0 mmol) were added. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The mixture was quenched with water and extracted with dichloromethane. The organic phase was collected and dried to obtain 700 mg of a crude product which was directly used in the next step.

[0223] (3) Preparation of tert-butyl 7-((5-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0224] 4-(6-(1H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (700 mg, 1.6 mmol) was dissolved in DMF (20 ml) at 20°C, cesium carbonate (1.6 g, 4.8 mmol) and tert-butyl 7-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (700 mg, crude) were added, and the mixture was reacted at 60°C for 8 h. LC-MS showed that the reaction was complete. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and purified by spin column chromatography (SiO2, petroleum ether:ethyl acetate=3:1) to obtain 500 mg of the product in a yield of 45.5%.

[0225] (4) Preparation of 4-(6-(1-((2-azaspiro[3.5]non-7-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0226] At 20°C, tert-butyl 7-((5-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 0.73 mmol) was dissolved in DCM (5 ml), trifluoroacetic acid (5 mL) was added, and the reaction was carried out at 25°C for 2 h. The reaction solution was spin-dried, acetonitrile (3 mL) and concentrated aqueous ammonia (6 mL) were added, and the reaction was carried out at 50°C for 12 hours. LCMS showed that the reaction was completed, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was collected to obtain 200 mg of a crude product, which was directly used in the next step.

[0227] (5) Preparation of 1-(7-((5-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.5]non-2-yl)prop-2-en-1-one

[0228] At 20°C, 4-(6-(1-((2-azaspiro[3.5]non-7-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (70 mg, crude product) was dissolved in DMF (5 ml), triethylamine (45 mg, 0.45 mmol) was added, acryloyl chloride (14 mg, 0.15 mmol) was dissolved in DMF, and the mixture was added dropwise to the system at 0°C. The mixture was reacted at 0°C for 1 h. LC-MS showed that the reaction was complete. Water was added, the mixture was extracted with EA, and the mixture was spin-dried. The product was analyzed by thin layer chromatography (DCM:MeOH=10:1) to obtain 10.0 mg of the product with a yield of 13.0%.

[0229] Molecular formula: C 29 H 33N7O2 molecular weight: 511.6 LC-MS (m / z): 512.3 (M+H + )

[0230] 1 H-NMR(400MHz,DMSO-d6)δ:12.21(s,1H),8.24(s,1H),8.21(s,1H),8.16( s,1H),8.01-7.92(m,1H),7.90-7.75(m,1H),7.13(s,1H),6.52-6.24(m,1 H)6.19-5.98(m,1H)5.79-5.54(m,1H),4.47(s,2H),3.89-3.87(m,6H),3. 74-3.72(m,6H),1.97-1.76(m,3H),1.54-1.21(m,4H),1.25-1.04(m,2H).

[0231] Example 2 Preparation of 1-(6-((5-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)prop-2-en-1-one (Compound 2)

[0232]

[0233] (1) Preparation of tert-butyl 6-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0234]

[0235] To a solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.2 mmol) in DCM (100 mL) was added TEA (445 mg, 4.4 mmol), and MsCl (287 mg, 2.5 mmol) was added dropwise at 25°C. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was washed once with 100 ml of water and once with 100 ml of saturated brine. The organic phase was spin-dried to give 677 mg of a crude product.

[0236] (2) Preparation of tert-butyl 6-((5-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl ester)-2-azaspiro[3.3]heptane-2-carboxylate

[0237] To a solution of 4-(6-(1H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (1.0 g, 2.2 mmol) in 30 ml of DMF was added 6-(((methylsulfonyl)oxy)methyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (677 mg, 2.2 mmol), potassium carbonate (608 mg, 4.4 mmol), and the mixture was reacted at 50° C. for 16 h. LC-MS showed that the reaction was complete. 150 ml of water was added to the reaction solution, and a solid was precipitated. The crude product was filtered out and purified by normal phase column (PE:EA=4:6) to obtain 600 mg of the product in a yield of 41.3%.

[0238] (3) Preparation of 4-(6-(1-((2-azaspiro[3.3]heptane-6-yl)methyl)-1H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0239] To a solution of tert-butyl 6-((5-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.45 mmol) in 10 ml of DCM was added 20 ml of TFA and the mixture was stirred at 25° C. for 1 h. LC-MS showed the reaction was complete and the reaction solution was evaporated to obtain 260 mg of a crude product.

[0240] (4) Preparation of 4-(6-(1-((2-azaspiro[3.3]heptane-6-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0241] To a solution of 4-(6-(1-((2-azaspiro[3.3]heptane-6-yl)methyl)-1H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (260 mg, crude product) in 10 ml of acetonitrile was added 20 ml of aqueous ammonia and the mixture was stirred at 25°C for 1 h. LC-MS showed that the reaction was complete and the reaction solution was evaporated to obtain 150 mg of a crude product.

[0242] (5) Preparation of 1-(6-((5-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-yl)prop-2-en-1-one

[0243] To a solution of 4-(6-(1-((2-azaspiro[3.3]heptane-6-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (43 mg, crude) in DMAc (10 ml) were added TEA (20 mg, 0.2 mmol) and acryloyl chloride (10 mg, 0.12 mmol) at 0°C. The mixture was reacted at 0°C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water to precipitate a solid, which was filtered to obtain a crude product. The crude product was separated using a normal phase column (SiO2, DCM:MeOH=90:10) to obtain 9 mg of the product.

[0244] Molecular formula: C 27 H 29 N7O2 molecular weight: 483.6 LC-MS (m / z): 484.4 (M+H + )

[0245] 1 H-NMR(400MHz,DMSO-d6)δ:12.21(s,1H),8.24(s,1H),8.16(s,1H),8.07(s,1H),7.96 -7.94(d,J=8.7,1H),7.76-7.74(d,J=8.7,1H),7.15(s,1H),6.25-6.23(m,1H),6.05- 6.01(m,1H),5.61-5.59(m,1H),4.41-4.40(m,2H),4.17(s,1H),4.08(s,1H),3.88-3. 87(m,5H),3.78-3.74(m,5H),2.69-2.65(m,1H),2.19-2.17(m,2H),2.05-1.97(m,2H).

[0246] Example 3 Preparation of 7-((5-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.5]nonane-2-carbonitrile (Compound 3)

[0247]

[0248] At 20°C, 4-(6-(1-((2-azaspiro[3.5]non-7-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (70 mg, crude product) was dissolved in DMF (5 ml), K2CO3 (62 mg, 0.45 mmol) was added, cyanogen bromide (16 mg, 0.15 mmol) was dissolved in DMF, and added dropwise to the system at 0°C, and reacted at 0°C for 1 h. LC-MS showed that the reaction was complete, water was added, EA was extracted, and the mixture was spin-dried. The product was obtained by thin layer chromatography (DCM:MeOH=10:1), 16.0 mg, and the yield was 22.1%. Molecular formula: C 27 H 30 N8O molecular weight: 482.6 LC-MS (m / z): 483.3 (M+H + )

[0249] 1 H-NMR(400MHz,DMSO-d6)δ:12.21(s,1H),8.24(s,1H),8.16(s,1H),8.15(s,1H),8.01-7.92(m,1H),7.90-7.75(m,1H),7 .13(s,1H),4.23(s,2H),3.89-3.87(m,6H),3.74-3.72(m,6H),1.97-1.76(m,3H),1.54-1.21(m,4H),1.25-1.04(m,2H).

[0250] Example 4 Preparation of 6-((5-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-indazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonitrile (Compound 4)

[0251]

[0252] At 0°C, potassium carbonate (27 mg, 0.2 mmol) and bromonitrile (13 mg, 0.12 mmol) were added to DMAc (10 ml) of 4-(6-(1-((2-azaspiro[3.3]heptane-6-yl)methyl)-1H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (43 mg, 0.1 mmol) and reacted at 0°C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water to precipitate solids. The crude product was filtered and separated by normal phase column (SiO2, DCM:MeOH=90:10) to obtain 11 mg of product with a yield of 24.2%. Molecular formula: C 25 H 26 N8O molecular weight: 454.5 LC-MS (m / z): 455.2 (M+H + )

[0253] 1 H-NMR (400MHz, DMSO-d6)δ:12.21(s,1H),8.24(s,1H),8.16(s,1H),8.07(s,1H),7.74-7.72(d,J=8.7,2H),7.14(s,1H),4.38-4.37(d,2 H),4.11-4.00(m,2H),3.89-3.88(d,2H),3.75-3.74(m,4H),3.74-3.73(m,4H),2.66-2.64(m,1H),2.21-2.03(m,2H),2.02-1.99(m,2H).

[0254] The above is a detailed introduction to the Menin inhibitor and its application provided by the present invention. The principles and implementation methods of the present invention are described in detail using specific examples herein. The description of the above examples is only used to help understand the method of the present invention and its central idea. It should be pointed out that for those of ordinary skill in the art, several improvements and modifications can 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, X1, X2, X4, Z2, and Z3 are independently selected from N or CR a ; X3 is selected from S, O, NR c or CR a R b ; Y1 and Z1 are independently selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 ; Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R c2 )-or-C(R a2 )(R b2 )-; R a1 , R b1 are independently selected from hydrogen, cyano, halogen, 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 The alkyl group is optionally substituted with one or more halogen, cyano or C 1-6 Alkyl substitution; R c , R c1 , each R c3 , R c4 are independently selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, -C(O)-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 ), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; Each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl, 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; m and q are each independently an integer from 0 to 4; n1 and n2 are each independently an integer from 0 to 3; n, n3, and n4 are each independently an integer of 1-4.

2. The compound according to claim 1, its pharmaceutically acceptable salt, ester or stereoisomer thereof, X1 and X2 are independently selected from N; X3 is selected from O, NR c or CR a R b ; X4 Selected from CR a ; Z2 and Z3 are independently selected from N or CR a ; Y1 and Z1 are independently selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 ; Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl or 5-8 membered heteroaryl; Each L is independently selected from -O-, -N(R c2 )-or-C(R a2 )(R b2 )-; R a1 , R b1 are independently selected from hydrogen, cyano, halogen, 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 C 1-6 The alkyl group is optionally substituted with 1 to 3 halogen, cyano or C 1-6 Alkyl substitution; R c , R c1 , each R c3 , R c4 are independently 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)-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 ), 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; Each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 , each R c2 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 alkyl; m and q are each independently an integer from 0 to 3; n1 and n2 are each independently an integer from 0 to 2; n, n3, and n4 are each independently an integer of 1-3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Select from the following structures: Y1 and Z1 are independently selected from CH or N; Y2 is selected from CR a1 R b1 or NR c1 ; Z2 and Z3 are independently selected from N or CR a ; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl; Each L is independently -C(R a2 )(R b2 )-; R a1 , R b1 are independently selected from hydrogen, cyano, 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 ); said C 1-4 The alkyl group is optionally substituted with 1-2 halogen, cyano or C 1-4 Alkyl substitution; Each R1, each R2, each R3, R a , each R a2 , each R a3 , each R b2 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; R c , R c1 , each R c3 , R c4 are independently selected from hydrogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-C 1-4 Alkoxy, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-C 1-4 Alkyl, -S(O)2-CH=CH2, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; m and q are independently 0, 1, and 2; n1 and n2 are independently 0, 1, and 2; n is 1, 2 or 3; n3 and n4 are independently 1 and 2, respectively.

4. The compound according to claim 3, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl; Each L is independently -C(R a2 )(R b2 )-; R a1 , R b1 are independently selected from hydrogen, cyano, -C(R 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)-C 1-4 Alkoxy, -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 ); Each R1, R2, each R3, each R a , R b , each R a2 , each R a3 , each R b2 , each R b3 Each of the following 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; R c , R c1 , each R c3 , R c4 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)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡ C(CH3), -C(O)-NH2, -S(O)2-CH3, -S(O)2-CH=CH2, 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl.

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, Ring A, Y1, Y2, each R1, R2, each R3, R a , R a1 , R a3 , R b1 , R b3 , R c , R c1 , R c3 , R c4 , n1, n2, n3, n4, m, q are defined as described in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxanyl, 1,3-dioxanyl, tetrahydropyranyl; Select from the following structures: Each R a1 , each R b1 Each of the following groups is 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)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -N(H)-C(O)-CH3, -N(H)-C(O)-CH2CH3, -N(CH3)-C(O)-CH2CH3, -N(H)-C(O)-H, -N(CH3)-C(O)-CH3, -N(H)-CN, -N(CH3)-CN; Each R c1 They are independently selected from hydrogen, cyano, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-O-CH3, -C(O)-O-CH2CH3, -C(O)-H, -C(O)-CH=CH2, -C(O)-C≡CH, -C(O)-C≡C(CH3), -C(O)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

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

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

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, 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.

10. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, ester or stereoisomer thereof, or the pharmaceutical preparation according to claim 8, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing a proliferative disease, an immune disease or an inflammatory disease.

Images