Spiro compound and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a spiro compound, pharmaceutically acceptable salt, ester or 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 a spirocyclic compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and use of the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof in preparing a drug for treating and / or preventing 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 spiro compound and its application. The specific technical scheme is as follows:

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

[0010]

[0011] Wherein, Z1, Z2, Z3, and Z4 are independently selected from CR a or N;

[0012] X1, X2, and X4 are 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, CR a1 R b1 or NR c1 ;

[0017] Y3, Y4, Y5, and Y6 are independently selected from CR a R b 、C(O)、S(O)2、O、S or NR c ;

[0018] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0019] Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R c2 )-、-C(R a2 )(R b2 )-;

[0020] 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;

[0021] Each R1, R2, each R3, each R a , each R b , each R a2 , each R b2 , each R a3 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C1-6 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, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0022] Each R c , each R c1 , each R c2 , each R c3 , each 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)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-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, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by 1-3 substituents, each of which is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0023] m and q are each independently an integer from 0 to 4;

[0024] n is an integer from 1 to 4;

[0025] n3 and n4 are each independently an integer of 1 to 4;

[0026] n1' and n2' are each independently selected from integers of 1-3.

[0027] 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 (I-1):

[0028]

[0029] Wherein, Z1, Z2, Z3, and Z4 are independently selected from CR a or N;

[0030] X1, X2, and X4 are independently selected from N or CR a ;

[0031] X3 is selected from S, O, NR c or CR a R b ;

[0032] Y1 is selected from CH or N;

[0033] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0034] Y3, Y4, Y5, and Y6 are independently selected from CR a R b 、C(O)、S(O)2、O、S or NR c ;

[0035] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0036] Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R c2 )-、-C(R a2 )(R b2 )-;

[0037] R a1 , R b1 are independently selected from hydrogen, cyano, halogen, C1-6 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;

[0038] Each R1, R2, each R3, each R a , each R b , each R a2 , each R b2 , each R a3 , each R b3 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, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0039] Each R c , each R c1 , each R c2 , each R c3 , each 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)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-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, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by 1-3 substituents, each of which 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;

[0040] m and q are each independently an integer from 0 to 4;

[0041] n is an integer from 1 to 4;

[0042] n3 and n4 are each independently an integer of 1 to 4;

[0043] n1' and n2' are each independently selected from integers of 1-3.

[0044] 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 (I):

[0045]

[0046] in,

[0047] X1, X2, and X4 are independently selected from N or CR a ;

[0048] X3 is selected from S, O, NR c or CR a R b ;

[0049] Y1 is selected from CH or N;

[0050] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0051] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0052] Each L is independently selected from -C(O)-, -O-, -S(O)-, -S(O)2-, -N(R c2 )-、-C(R a2 )(R b2 )-;

[0053] R a1 , Rb1 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)-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;

[0054] Each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3 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, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-8 membered heteroaryl;

[0055] R c , R c1 , each R c2 , each R c3 , each 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)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-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, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by 1-3 substituents, each of which 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;

[0056] m and q are each independently an integer from 0 to 4;

[0057] n is an integer from 1 to 4;

[0058] n1 and n2 are each independently an integer from 0 to 3;

[0059] n3 and n4 are each independently an integer of 1-4.

[0060] In certain embodiments, X1 and X2 are independently selected from N; X3 is selected from O, NR c or CR a R b ; X4 is selected from N or CR a .

[0061] In certain embodiments, Y1 is selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 .

[0062] 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.

[0063] In certain embodiments, Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0064] 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- Dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, tetrahydro-2H-thiopyran 1,1-dioxide, thiomorpholin-3-one 1,1-dioxide, dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide, 3,6-dihydro-2H-thiopyran 1,1-dioxide, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 3-morpholinone, morpholine-3,5-dione.

[0065] In certain embodiments, ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,3-dioxanyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl,

[0066]

[0067] In certain embodiments, each L is independently selected from -C(O)-, -N(R c2 )-、-C(R a2 )(R b2 )-, -S(O)2-.

[0068] In certain embodiments, -(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 )-.

[0069] In certain embodiments, -(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)-.

[0070] 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 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 1-6 The alkyl group is optionally substituted with 1 to 3 halogen, cyano or C 1-6 Alkyl substitution.

[0071] 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 )(Rb3 )、-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.

[0072] 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)-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.

[0073] 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)-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, -C(O)-O-CH2CH3.

[0074] In certain embodiments, each R1, R2, each R3, each R a , Rb , each R a2 , each R b2 , each R a3 , each R b3 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 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0075] In certain embodiments, each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group.

[0076] In certain embodiments, each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3Each of them 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.

[0077] In certain embodiments, R c , R c1 , each R c2 , each R c3 , each 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, C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 ), -S(O)2-R a3 、-S(O)2-C(R a3 )=C(R a3 )(R b3 ), 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are 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.

[0078] In certain embodiments, R c , R c1 , each R c2 , each R c3 , each 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 a2 )(R b2 )-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 ), -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are 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.

[0079] In certain embodiments, R c , R c1 , each R c2 , each R c3 , each 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)-CH2-R a3 、-C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C1-4 Alkoxy.

[0080] In certain embodiments, R c , R c1 , each R c2 , each R c3 , each 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)-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, -S(O)2-R a3 , -S(O)2-CH=CH2, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, heteroaryl, heterocyclic group are optionally substituted by 1-3 substituents, the substituents are independently selected from halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy.

[0081] In certain embodiments, R c , R c1 , each R c3 , each 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)-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)-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, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl.

[0082] In certain embodiments, R c , R c1 , each R c3 , each R c4 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)-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)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl.

[0083] In certain embodiments, m and q are each independently an integer of 0-3; n is an integer of 1-3;

[0084] n1 and n2 are each independently an integer of 0-2; n3 and n4 are each independently an integer of 1-3.

[0085] In certain embodiments, m and q are independently 0, 1, or 2; n is 1, 2, or 3;

[0086] n1 and n2 are independently 0, 1, and 2 respectively; n3 and n4 are independently 1 and 2 respectively.

[0087] In certain embodiments, n1' and n2' are independently 1, 2, or 3.

[0088] Select from the following structures:

[0089] Each R2, each R a , each R c The definition of is as described in any of the above technical solutions.

[0090] In certain embodiments,

[0091] Select from the following structures:

[0092] Each R2, R a , each R c The definition of is as described in any of the above technical solutions.

[0093] In certain embodiments, Y3, Y4, Y5, and Y6 are each independently selected from CR a R b , O, S or NR c ;

[0094] Y1 is selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 .

[0095] In certain embodiments, Y3, Y4, Y5, and Y6 are each independently selected from CR a R b or NR c ;

[0096] Y1 is selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 .

[0097] In certain embodiments,

[0098] Select from the following structures:

[0099]

[0100] Each R a1 , each R b1 , each R c1 The definition of is as described in any of the above technical solutions.

[0101] In certain embodiments,

[0102] Select from the following structures:

[0103]

[0104] Each R a1 , each R b1 , each R c1 The definition of is as described in any of the above technical solutions.

[0105] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0106] X1 and X2 are independently selected from N;

[0107] X3 is selected from O, NR c or CR a R b ;

[0108] X4 is selected from N or CR a ;

[0109] Y1 is selected from CH or N;

[0110] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0111] Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl or 5-8 membered heteroaryl;

[0112] Each L is independently selected from -C(O)-, -N(R c2 )-、-C(R a2 )(R b2 )-, -S(O)2-;

[0113] 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;

[0114] Each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3 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 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0115] R c , R c1 , each R c2 , each R c3 , each 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 a2 )(R b2 )-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 ), -S(O)2-R a3 、-S(O)2-C(R a3 )=C(Ra3 )(R b3 ), 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0116] m and q are each independently an integer from 0 to 3;

[0117] n is an integer from 1 to 3;

[0118] n1 and n2 are each independently an integer from 0 to 2;

[0119] n3 and n4 are each independently an integer of 1-3.

[0120] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0121] Select from the following structures:

[0122]

[0123] Y1 is selected from CH or N;

[0124] Y2 is selected from O, CR a1 R b1 or NR c1 ;

[0125] Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0126] -(L)n- is selected from -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(Ra2 )(R b2 )-C(R a2 )(R b2 )-、-C(O)-N(R c2 )-;

[0127] 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;

[0128] Each R1, each R2, each R3, R a , each R a2 , each R b2 , each R a3 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group;

[0129] R c , R c1 , each R c2 , each R c3 , each Rc4 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)-CH2-R a3 、-C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are 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;

[0130] m and q are independently 0, 1, and 2;

[0131] n1 and n2 are independently 0, 1, and 2;

[0132] n3 and n4 are independently 1 and 2, respectively.

[0133] 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 (I-1):

[0134]

[0135] Wherein, Z1, Z2, Z3, and Z4 are independently selected from CR a or N;

[0136] Y3, Y4, Y5, and Y6 are independently selected from CR a R b 、C(O)、S(O)2、O、S or NR c ;

[0137] n1' and n2' are independently selected from integers of 1-3;

[0138] Ring A, X1, X2, X3, X4, each L, Y1, Y2, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , each R b , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0139] 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 (I-2):

[0140]

[0141] Wherein, Z1 and Z2 are independently selected from CR a or N;

[0142] Y3 is selected from CR a R b , C(O) or NR c ;

[0143] n1' and n2' are independently selected from integers of 1-3;

[0144] Ring A, X1, X2, X3, X4, each L, Y1, Y2, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , R b , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0145] 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 (I-3):

[0146]

[0147] Wherein, Z1 and Z2 are independently selected from CR a or N;

[0148] Y3 is selected from CR a R b , C(O) or NR c ;

[0149] Ring A, X1, X2, X3, X4, each L, Y1, Y2, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , R b , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0150] In certain embodiments,

[0151] are independently selected from the following structures:

[0152]

[0153]

[0154] Each R a1 , each R b1 , each R c1 The definition of is as described in any of the above technical solutions.

[0155] 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 (I-4):

[0156]

[0157] Among them, ring A, X1, X2, X3, X4, each L, Y1, Y2, Y5, Y6, Z1, Z2, Z3, Z4, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , R b1, each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1', n2', n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0158] 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 (I-5):

[0159]

[0160] Wherein, Z1 and Z2 are independently selected from CR a or N;

[0161] Ring A, X1, X2, X3, X4, each L, Y1, Y2, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0162] 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 (I-6):

[0163]

[0164] Wherein, Z1 and Z2 are independently selected from CR a or N;

[0165] Ring A, X4, each L, Y1, Y2, Y3, each R1, R2, each R3, each R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1, each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0166] 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 (I-7):

[0167]

[0168] Among them, ring A, X4, each L, Y1, each R1, R2, each R3, R a , each R a2 , each R b2 , R c1 , each R c2 , n1, n2, m, n, q are defined as described in any of the preceding schemes.

[0169] 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):

[0170]

[0171] Among them, ring A, each L, Y1, Y2, each R1, R2, each R3, R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0172] 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-1) or formula (II-3):

[0173]

[0174] Among them, ring A, X4, each L, Y1, Y2, each R1, R2, each R3, R a , R a1 , each R a2, each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0175] 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-2):

[0176]

[0177] Among them, ring A, X4, each L, Y1, Y2, each R1, R2, each R3, R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 The definitions of m, n, and q are as described in any of the preceding schemes.

[0178] 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) or formula (III-1):

[0179]

[0180] Among them, ring A, 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 , each R c4 , n1, n2, n3, n4, m, q are defined as described in any of the preceding schemes.

[0181] 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) or formula (IV-1):

[0182]

[0183] Among them, Y1, Y2, R2, 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.

[0184] 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), formula (V-1), formula (V-2) or formula (V-3):

[0185]

[0186]

[0187] Among them, Y1, Y2, each R1, R2, each R3, R a , R c , R a1 , R b1 , R c1 , each R a3 , each R b3 , each R c3 , each R c4 is defined as described in any of the preceding schemes.

[0188] 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 (VI) or formula (VI-1):

[0189]

[0190] Among them, Y1, R2, each R3, R a , R c , R c1 , m are defined as described in any of the aforementioned schemes.

[0191] 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 (VII):

[0192]

[0193] Among them, each L, Y1, Y2, each R1, R2, each R3, R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1, n2, n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0194] 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 (VIII):

[0195]

[0196] Among them, each L, Y1, Y2, each R1, R2, each R3, R a , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 The definitions of m, n, and q are as described in any of the preceding schemes.

[0197] 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 (IX):

[0198]

[0199] X5 is selected from N or CR2;

[0200] Among them, ring A, X1, X2, X3, X4, each L, Y1, Y2, Y3, Y4, Y5, Y6, each R1, R2, each R3, each Ra , R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c , R c1 , each R c2 , each R c3 , each R c4 , n1', n2', n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0201] 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 (IX-1):

[0202]

[0203] Among them, ring A, each L, Y1, Y2, Y3, Y4, Y5, Y6, each R1, each R3, R a1 , each R a2 , each R a3 , R b1 , each R b2 , each R b3 , R c1 , each R c2 , each R c3 , each R c4 , n1', n2', n3, n4, m, n, q are defined as described in any of the preceding schemes.

[0204] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0205] Ring A is selected from cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine-1,1-dioxide, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophene 1,1-dioxide, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 3-morpholinone, morpholine-3,5-dione;

[0206] -(L)n- is selected from -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)-;

[0207] 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;

[0208] Each R1, R2, each R3, R a , R b , each R a3 , 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, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0209] R c , R c1 , each R c3 , each 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)-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)-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, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl.

[0210] In certain embodiments, the compound shown in the above scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein,

[0211] Ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxane, 1,3-dioxane, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl,

[0212]

[0213] Select from the following structures:

[0214] 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)-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, -C(O)-O-CH2CH3;

[0215] Each R c1 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)-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)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl.

[0216] In certain embodiments, the compound shown in the foregoing scheme, its pharmaceutically acceptable salt, ester or stereoisomer thereof,

[0217] Wherein, ring A is selected from cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxane, 1,3-dioxane, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl,

[0218]

[0219] Select from the following structures:

[0220] Each R a1 , each R b1 are independently selected from hydrogen, cyano, -C(R a3 )(R b3 )-N(R c3 )-C(O)-C(R a3 )=C(Ra3 )(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 1-4 The alkyl group is optionally substituted with 1-2 halogen, cyano or C 1-4 Alkyl substitution;

[0221] R c , each R c1 , each R c3 , each 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 a2 )(R b2 )-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 ), -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0222] Each R1, each R2, each R3, R a , R b , each R a3 , each Rb3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group;

[0223] m and q are independently 0 and 1, respectively.

[0224] In certain embodiments, the compound shown in the aforementioned scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Ring A is selected from a 5-6 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group;

[0225] Select from the following structures:

[0226] Select from the following structures:

[0227]

[0228] R a , R c , R2, each R a1 , each R b1 , each R c1 The definition of is as described in any of the above technical solutions.

[0229] In some embodiments of the present invention, the structure of the provided compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof is as follows:

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] The present invention also provides a pharmaceutical composition, which contains the compound represented by the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents. Optionally, the pharmaceutical composition also contains one or more pharmaceutically acceptable carriers and / or diluents.

[0238] 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.

[0239] The present invention also provides a pharmaceutical preparation, which contains the compound represented by the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is in any dosage form that is clinically or pharmaceutically acceptable.

[0240] 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.

[0241] 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.

[0242] The present invention also provides the use of the compound represented by the aforementioned general formula, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of drugs for treating and / or preventing proliferative diseases, immune diseases, and inflammatory diseases.

[0243] The present invention also provides a method for treating a disease, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by the aforementioned general formula, its 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0248] 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.

[0249] 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 2-6Alkyl", "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.

[0250] 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 2-3 Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3- ...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.

[0251] 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 2-4Alkynyl", "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.

[0252] The “C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylamino, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylcarbonyl, C 1-6 "Alkyloxycarbonyl" refers to a 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 The group formed by alkyl-OC(O)-, wherein "C 1-6 "Alkyl" is as defined above.

[0253] The “C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, 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-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 1-4The group formed by alkyl-OC(O)-, wherein "C 1-4 "Alkyl" is as defined above.

[0254] 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.

[0255] The "halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl, halogenated C 1-4 "Alkoxy" refers to one or more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, etc., which are substituted by C 1-4 Alkyl, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0256] The "3-10 membered cycloalkyl" 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" and "condensed cyclic alkyl". Among them, "monocyclic alkyl" refers to a saturated or partially saturated monocyclic cyclic alkyl group without aromaticity, 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", The cycloalkyl group may be any of the following: 6-7 membered cycloalkyl group", "6-8 membered cycloalkyl group", "7-8 membered cycloalkyl group", "3-6 membered saturated cycloalkyl group", "4-7 membered saturated cycloalkyl group", "4-8 membered saturated cycloalkyl group", "5-8 membered saturated cycloalkyl group", "5-7 membered saturated cycloalkyl group", "5-6 membered saturated cycloalkyl group", "3-6 membered partially saturated cycloalkyl group", "4-7 membered partially saturated cycloalkyl group", "4-8 membered partially saturated cycloalkyl group", "5-8 membered partially saturated cycloalkyl group", "5-7 membered partially saturated cycloalkyl group", "5-6 membered partially saturated cycloalkyl group", 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, 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, and the like.The term "condensed cycloalkyl" 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 condensed rings may be an aromatic ring, but the condensed ring as a whole does not have 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, 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.

[0257] The "3-10 membered heterocyclic group" described in the present invention refers to a saturated or partially saturated, non-aromatic monocyclic or condensed ring group containing at least one heteroatom (for example, 1, 2, 3, 4 or 5) and 3-10 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms in the ring structure (such as carbon atoms, nitrogen atoms or sulfur atoms) may be oxidized. It includes "3-10 membered saturated heterocyclic group" and "3-10 membered partially saturated heterocyclic group". Preferably, the "3-10 membered heterocyclic group" described in the present invention contains 1-3 heteroatoms; preferably, the "3-10 membered heterocyclic group" described in 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. Preferred are "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 the like. Specific examples 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, morpholine 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-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-dione, pyrrolidinylcyclopropyl, cyclopentylaziridinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl , pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridotisoxazolidinyl, pyridothiazolidinyl, pyridopiperdinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidotisoxazolidinyl, pyrimidothiazolidinyl, pyrimidopiperdinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl;tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- 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, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc. ;

[0258] The "6-10 membered aryl" described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl". The "6-8 membered monocyclic aryl" refers to a monocyclic aryl containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl. The "8-10 membered condensed ring aryl" refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms formed by two or more ring structures sharing two adjacent atoms, preferably a "9-10 membered condensed ring aryl", and specific examples include naphthyl, etc.

[0259] The "5-10 membered heteroaryl" of the present invention refers to an aromatic cyclic group containing 5-10 ring atoms (wherein at least one ring atom 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". Among them, "5-8 membered single heteroaryl" refers to an aromatic monocyclic cyclic group containing 5-8 ring atoms (wherein at least one ring atom 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 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", etc. 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 "5-6 membered heteroaryl" refers to a specific example of a 5-8 membered heteroaryl containing 5-6 ring atoms. The "8-10 membered fused heteroaryl" 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.

[0260] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0261] 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.

[0262] 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).

[0263] 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.

[0264] 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.

[0265] Advantageous Effects of the Invention

[0266] (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;

[0267] (2) The compounds of the present invention have a good inhibitory effect on tumor cells;

[0268] (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;

[0269] (4) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0270] (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.

[0271] 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.

[0272] Experimental Example 1 In vitro cytological activity of the compounds of the present invention

[0273] Test samples: some compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0274] Cell lines used in the experiment:

[0275] MIA PaCa-2: KRAS G12C mutant human pancreatic cancer cells HCT116: KRAS G13D mutant human colon cancer cells

[0276] Experimental method (CelltiterGlo assay)

[0277] 1. Cell Preparation

[0278] 1.1 Cell culture:

[0279] 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.

[0280] 1.2 Preparation of cell suspension:

[0281] 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.

[0282] Table 1 Number of cells seeded

[0283]

[0284] 2. Preparation of test compounds

[0285] 2.1 Preparation of test compound stock solution

[0286] Test compounds were prepared in DMSO to 10 mM as assay stock solutions.

[0287] 2.2 Preparation of test compound working solution

[0288] 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).

[0289] 2.3 Compound treatment

[0290] 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.

[0291] 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.

[0292] 2.4 Control well setting

[0293] Solvent control: 0.1% DMSO;

[0294] Blank control: culture medium.

[0295] 2.5 Cultivation

[0296] The 96-well plate was placed in a 37°C, 5% CO2 cell culture incubator and cultured for 4 days.

[0297] 3. Detection

[0298] 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.

[0299] 4. Data Processing

[0300] 1) Inhibition rate (%) = 1-(test well reading-blank control well reading) / (DMSO solvent control well reading-blank control well reading) × 100%;

[0301] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0302] Experimental results and conclusions

[0303] 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 +++.

[0304] Table 2. In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0305]

[0306]

[0307] 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.

[0308] Experimental Example 2 In vitro cell inhibition activity of the compounds of the present invention

[0309] Test substances Some of the compounds of the present invention, their chemical names and structures are shown in the preparation examples.

[0310] The cell lines used in the following experiments are as follows:

[0311] MV-4-11: Human myelomonocytic leukemia cells with rearranged MLL gene

[0312] Toledo: Human diffuse large B-cell lymphoma cells with C-MYC and BCL-2 gene translocation

[0313] Experimental method (CelltiterGlo assay)

[0314] 1. Cell Preparation

[0315] 1.1 Cell culture:

[0316] All cells were suspension cells, the culture medium for MV-4-11 cells was IMEM medium + 20% FBS + 1% PS, and the culture medium for Toledo cells was RPMI Medium 1640 (1X) medium + 20% FBS + 1% PS. The cells were tested in the logarithmic growth phase.

[0317] 1.2 Preparation of cell suspension:

[0318] 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.

[0319] Table 3. Cell seeding number

[0320]

[0321] 2. Preparation of test compounds

[0322] 2.1 Preparation of test compound stock solution

[0323] Test compounds were prepared in DMSO to 10 mM as assay stock solutions.

[0324] 2.2 Preparation of test compound working solution

[0325] 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).

[0326] 2.3 Compound treatment

[0327] 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.

[0328] 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.

[0329] 2.4 Control well setting

[0330] Solvent control: 0.1% DMSO;

[0331] Blank control: culture medium.

[0332] 2.5 Cultivation

[0333] The 96-well plate was placed in a 37°C, 5% CO2 cell culture incubator and cultured for 4 days.

[0334] 3. Detection

[0335] 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.

[0336] 4. Data Processing

[0337] 1) Inhibition rate (%) = 1-(test well reading-blank control well reading) / (DMSO solvent control well reading-blank control well reading) × 100%;

[0338] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0339] Experimental results and conclusions

[0340] Table 4. In vitro cytological activities of the compounds of the present invention (IC 50 ,nM)

[0341]

[0342] As shown in Table 4, the compounds of the present invention can effectively inhibit the proliferation of MV-4-11 and Toledo cells, indicating that the compounds of the present invention have clinical application potential in treating cancerous diseases with MLL gene rearrangement and C-MYC and BCL-2 gene translocation. DETAILED DESCRIPTION

[0343] 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.

[0344] The abbreviations used in the following experiments have the following meanings:

[0345] DIEA: N,N-diisopropylethylamine; EA: ethyl acetate; PE: petroleum ether; NMP: N-methylpyrrolidone;

[0346] THF: tetrahydrofuran; DCM: dichloromethane; DMF: N,N-dimethylformamide; TFA: trifluoroacetic acid.

[0347] Example 1 Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide (Compound 1)

[0348]

[0349] (1) Preparation of phenyl (4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0350] 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (100 mg, 0.34 mmol), DIEA (129 mg, 1.0 mmol) and phenyl chloroformate (52 mg, 0.34 mmol) were dissolved in THF (20 mL) and reacted at 25 ° C for 1 h. After the reaction was completed, the reaction solution was spin-dried and the residue was purified by column chromatography (SiO2, MeOH:DCM=1:10) to obtain 100 mg of the product with a yield of 70.8%.

[0351] (2) Preparation of tert-butyl 7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0352] Phenyl (4- (4-morpholinyl-7H-pyrrolo [2,3-d] pyrimidin-6-yl) phenyl) carbamate (300 mg, 0.72 mmol) was dissolved in acetonitrile (10 mL), tert-butyl 2,7-diazaspiro [3.5] nonane-2-carboxylate (249 mg, 1.1 mmol) and potassium carbonate (304 mg, 2.2 mmol) were added, and the mixture was reacted at 80 ° C for 12 h. After the reaction was completed, the reaction solution was spin-dried and purified by column chromatography (SiO2, MeOH: DCM = 1: 10) to obtain 150 mg of the product with a yield of 38.1%.

[0353] (3) Preparation of N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0354] To tert-butyl 7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (150 mg, 0.27 mmol) was added HCl / EtOH (4 M, 20 mL), and the mixture was reacted at 20° C. for 2 h. LC-MS showed that the reaction was completed. The reaction solution was spin-dried to give 100 mg of a crude product.

[0355] (4) Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0356] Potassium carbonate (74 mg, 0.54 mmol) and bromocyanide (19 mg, 0.18 mmol) were added to a solution of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide (80 mg, crude product) in DMF (10 ml) at 20°C. The mixture was reacted at 20°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 8 mg of the product with a two-step yield of 6.3%.

[0357] 1H-NMR(400MHz, DMSO-d6)δ:12.06(s,1H),8.58(s,1H),8.14(s,1H),7.76-7.75(d,J=8.7,2H),7.51-7.49(d,J=8.7,2H),7.02( s,1H),3.90-3.89(m,4H),3.85-3.80(m,4H),3.73-3.69(m,4H),3.36-3.32(m,4H),1.72-1.70(m,4H).LC-MS(M / e):473.4(M+H + ).

[0358] Example 2 Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (Compound 2)

[0359]

[0360] (1) Preparation of tert-butyl 7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0361] To a solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (135 mg, 0.5 mmol) in THF (100 mL) were added 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (148 mg, 0.5 mmol), HATU (285 mg, 0.75 mmol) and DIEA (97 mg, 0.75 mmol). The mixture was reacted at 25°C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water and extracted with DCM. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=10:90) to give 260 mg of a crude product.

[0362] (2) Preparation of N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide

[0363] To tert-butyl 7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate (200 mg crude product) was added HCl / EtOH (4M, 40 mL), and the reaction was carried out at 20°C for 2 h. LC-MS showed that the reaction was completed. The reaction solution was spin-dried to obtain a crude product. Saturated aqueous sodium bicarbonate solution was added to adjust the pH value to 8. The solvent was removed by rotary evaporation, and the product was eluted with DCM:MEOH=12:1. The product was spin-dried to obtain 150 mg, and the yield of two steps was 67.2%.

[0364] (3) Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide

[0365] 49 mg of the product was prepared in step (4) of Reference Example 1 with a yield of 38.5%.

[0366] 1 H-NMR (400MHz, DMSO-d6)δ:12.10(s,1H),9.90(s,1H),8.15(s,1H),7.82-7.79(d,J=8.7,2H),7.63-7.61(d,J=8.7,2H), 7.06-7.05(s,1H),3.88-3.74(m,8H),3.72-3.71(m,4H),2.33-2.30(m,1H),1.99(m,2H),1.74(m,2H),1.42-1.39(m,4H). LC-MS(m / z):472.3(M+H + ).

[0367] Example 3 Preparation of 3-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide (Compound 4)

[0368]

[0369] (1) Preparation of tert-butyl 9-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0370] To a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (244 mg, 0.82 mmol) in DMF (10 mL) were added 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (200 mg, 0.68 mmol), HATU (760 mg, 2.0 mmol) and triethylamine (485 mg, 4.8 mmol). The mixture was reacted at 25° C. for 12 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, and solid precipitated. The solid was filtered and collected. The obtained solid was slurried with methanol to obtain 250 mg of the product with a yield of 64.0%.

[0371] (2) Preparation of N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide

[0372] To tert-butyl 9-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate (250 mg, 0.43 mmol) was added HCl / EtOH (4 M, 20 mL), and the reaction was carried out at 20°C for 2 h. LC-MS showed that the reaction was completed. The reaction solution was spin-dried to obtain a crude product. Saturated aqueous sodium bicarbonate was added to adjust the pH value to 8, and the product was evaporated to dryness. The residue was eluted with DCM:MEOH=12:1 and spin-dried to obtain 150 mg of the product with a yield of 72.7%.

[0373] (3) Preparation of 3-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide

[0374] 16 mg of product was prepared in step (4) of Reference Example 1 with a yield of 21.4%.

[0375] 1 H-NMR (400MHz, DMSO-d6)δ:12.10(s,1H),9.90(s,1H),8.15(s,1H),7.82-7.79(d,J=8.7,2H),7.63-7.61(d,J=8.7,2H),7.06-7.05(s,1H) ,3.88-3.74(m,8H),3.29-3.11(m,4H),2.33-2.30(m,1H),1.99-1.80(m,2H),1.74-1.51(m,6H),1.42-1.01(m,4H).LC-MS(m / z):500.3(M+H) + ).

[0376] Example 4 Preparation of 2-amino-N-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (Compound 5)

[0377]

[0378] (1) Preparation of ethyl 2-(benzylamino)spiro[3.5]nonane-7-carboxylate

[0379] Ethyl 2-oxospiro[3.5]nonane-7-carboxylate (800 mg, 3.8 mmol) was dissolved in 10 mL of methanol, and acetic acid (1 mL), benzylamine (640 mg, 6.0 mmol) and sodium cyanoborohydride (1.2 g, 19.1 mmol) were added to the system and reacted at 25° C. for 6 hours. After concentration, the pH of the system was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether=0-50%) to obtain 450 mg of the product with a yield of 39.2%.

[0380] (2) Preparation of ethyl 2-(benzyl(tert-butyloxycarbonyl)amino)spiro[3.5]nonane-7-carboxylate

[0381] Ethyl 2-(benzylamino)spiro[3.5]nonane-7-carboxylate (350 g, 1.2 mmol) was dissolved in DCM (20 mL), and triethylamine (250 mg, 2.5 mmol) and Boc2O (300 mg, 1.4 mmol) were added. The system was reacted at 20°C for 1 hour and then directly concentrated. The mixture was washed with water, extracted with ethyl acetate, and concentrated. The crude product was directly used for the next reaction.

[0382] (3) Preparation of 2-(Benzyl(tert-butyloxycarbonyl)amino)spiro[3.5]nonane-7-carboxylic acid

[0383] The crude product from the previous step was dissolved in methanol (10 mL), water (10 mL) and tetrahydrofuran (10 mL), and LiOH·H2O (260 mg, 6.2 mmol) was added to react at 25°C for 2 h. After the reaction was completed, the pH of the system was adjusted to 6 with 4M HCl, and the mixture was concentrated. The residue was purified by reverse phase column chromatography (MeOH:H2O=0-50%) to obtain 300 mg of the product. The yield of the two steps was 69.2%.

[0384] (4) Preparation of (tert-butylbenzyl (7-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)spiro[3.5]nonan-2-yl)carbamate

[0385] 2-(Benzyl(tert-butoxycarbonyl)amino)spiro[3.5]nonane-7-carboxylic acid (260 mg, 0.70 mmol), 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (210 mg, 0.71 mmol), triethylamine (355 mg, 3.5 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (540 mg, 1.4 mmol) were dissolved in DMF (10 mL) and reacted at 25° C. for 2 h. After the reaction was completed, water and ethyl acetate were added for extraction, the organic phase was collected, concentrated, and 310 mg of the product was obtained by column chromatography (MeOH:DCM=1:10). The yield was 68.4%.

[0386] (5) Preparation of tert-butyl (7-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)spiro[3.5]nonan-2-yl)carbamate

[0387] Dissolve (tert-butylbenzyl(7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)spiro[3.5]nonan-2-yl)carbamate (160 mg, 0.25 mmol) in methanol (10 mL), add concentrated hydrochloric acid 0.5 mL and Pd / C (160 mg), react at 50 ° C under H2 protection for 6 h. After the reaction is completed, the concentrated crude product is directly used in the next reaction.

[0388] (6) Preparation of 2-amino-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide hydrochloride

[0389] The crude product from the previous step was dissolved in 4M HCl / Dioxane (10 mL) and reacted at 25°C for 2 h. After the reaction was completed, the mixture was concentrated and used directly in the next step.

[0390] (7) Preparation of 2-amino-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0391] Triethylamine (100 mg, 0.99 mmol) and acryloyl chloride (25 mg, 0.28 mmol) were added to DCM (5 ml) and DMF (5 mL) of the crude product from the previous step, and the mixture was reacted at -10°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM / MeOH (10 / 1). The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 55 mg of the product.

[0392] 1H-NMR(400MHz,DMSO-d6)δ:12.12(s,1H),9.91(s,1H),8.29(s,1H),8.28(s,1H),7.81(d,J =8.7,2H),7.67(d,J=8.7,2H),7.07(s,1H)6.20-6.10(m,1H),6.10-5.98(m,1H),5.70-5.55 (m,1H),4.22-4.10(m,1H),3.94-3.80(m,4H),3.80-3.69(m,4H),2.30-2.20(m,2H),2.10-2 .00(m,1H),1.91-1.81(m,1H)1.70-1.30(m,8H),1.30-1.20(m,1H).LC-MS(M / e):515.2(M+H + ).

[0393] Example 5 Preparation of 2-(N-methylacrylamide)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (Compound 7)

[0394]

[0395] (1) Preparation of ethyl 1,1-dichloro-2-oxospiro[3.5]nonane-7-carboxylate

[0396] 2,2,2-trichloroacetyl chloride (108.1 g, 594.6 mmol) was added dropwise to a solution of ethyl 4-methylenecyclohexane-1-carboxylate (20.0 g, 118.9 mmol) and Zn-Cu couple (137.9 g, 1069.8 mmol) in THF (900 mL) at 0°C. After the addition was complete, the mixture was reacted at 15°C for 18 h. TLC (PE:EA=10:1) showed that the reaction was complete. Water and EA were added to the reaction solution at 0°C for dilution, the mixture was stirred for 0.5 h, filtered, the organic phase was spin-dried, and the residue was separated by column chromatography (SiO2, PE:EA=95:5) to give 8.0 g of product with a yield of 24.1%.

[0397] (2) Preparation of ethyl 2-oxospiro[3.5]nonane-7-carboxylate

[0398] Zinc powder (9.4 g, 143.7 mmol) was added to a solution of ethyl 1,1-dichloro-2-oxospiro[3.5]nonane-7-carboxylate (8.0 g, 28.7 mmol) in AcOH (100 mL), and the reaction was carried out at 80°C for 13 h. LCMS showed that the reaction was complete. The reaction solution was filtered, the filtrate was dried, the residue was diluted with DCM, washed with saturated sodium bicarbonate solution, the organic phase was dried, and the residue was separated by column chromatography (SiO2, PE:EA=10:1) to obtain 4.8 g of the product with a yield of 79.7%.

[0399] (3) Preparation of ethyl 2-(methylamino)spiro[3.5]nonane-7-carboxylate

[0400] Methylamine hydrochloride (142 mg, 2.1 mmol), potassium acetate (412 mg, 4.2 mmol) and sodium cyanoborohydride (264 mg, 4.2 mmol) were added to a solution of ethyl 2-oxospiro[3.5]nonane-7-carboxylate (300 mg, 1.4 mmol) in methanol (6 mL). The mixture was reacted at 15 °C for 16 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with DCM, and the organic phase was spin-dried to give 300 mg of a crude product.

[0401] (4) Preparation of ethyl 2-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonane-7-carboxylate

[0402] Triethylamine (395 mg, 3.9 mmol) and Boc2O (568 mg, 2.6 mmol) were added to a solution of ethyl 2-(methylamino)spiro[3.5]nonane-7-carboxylate (300 mg crude product) in DCM (3 mL) and methanol (3 mL). The mixture was reacted at 20°C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to give 600 mg crude product.

[0403] (5) Preparation of 2-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonane-7-carboxylic acid

[0404] To a solution of ethyl 2-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonane-7-carboxylate (600 mg crude product) in methanol (10 mL) was added a solution of lithium hydroxide (800 mg, 33.3 mmol) in water (2 mL), and the mixture was reacted at 20° C. for 2 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was diluted with water. The pH was adjusted to 5 with dilute hydrochloric acid (2 M), and the mixture was extracted with DCM. The organic phase was spin-dried to give 300 mg of a crude product.

[0405] (6) Preparation of tert-butyl methyl(7-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)spiro[3.5]nonan-2-yl)carbamate

[0406] To a solution of 2-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonane-7-carboxylic acid (300 mg crude product) in DMF (10 mL) were added 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (300 mg, 1.0 mmol), HATU (760 mg, 2.0 mmol) and DIEA (388 mg, 3.0 mmol). The mixture was reacted at 20° C. for 14 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, stirred for 0.5 h, filtered, and the filter cake was dried to obtain 200 mg of a crude product.

[0407] (7) Preparation of 2-(methylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0408] To tert-butyl methyl(7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)spiro[3.5]nonan-2-yl)carbamate (200 mg crude product) in methanol (5 mL) was added HCl / dioxane (4 M, 5 mL), and the reaction was carried out at 20° C. for 1 h. LC-MS showed that the reaction was completed. The reaction solution was spin-dried to give 150 mg of a crude product.

[0409] (8) Preparation of 2-(N-methylacrylamide)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0410] To a solution of 2-(methylamino)-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (150 mg crude product) in DCM (3 ml) and DMF (3 mL) were added DIEA (200 mg, 1.5 mmol) and acryloyl chloride (30 mg, 0.33 mmol) at -10°C, and the mixture was reacted at -10°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM / MeOH (10 / 1). The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, DCM:MeOH=96:4) to give a crude product of 100 mg. The product was slurried with MeOH, filtered, and the filter cake was dried to give 80 mg of the product.

[0411] 1H-NMR(400MHz,DMSO-d6)δ:12.12(s,1H),9.91(s,1H),8.15(s,1H),7.80(d,J=8.7,2H), 7.63(d,J=8.7,2H),7.07(s,1H),6.80-6.60(m,1H),6.10-5.98(m,1H),5.70-5.55(m,1H) ,4.97-4.40(m,1H),3.94-3.80(m,4H),3.80-3.69(m,4H),2.97-2.80(m,3H),2.30-2.20 (m,1H),2.00-1.80(m,5H),1.76-1.60(m,3H),1.50-1.30(m,4H).LC-MS(m / z):529.2(M+H + ).

[0412] Example 6 Preparation of 3-acryloyl-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide (Compound 9)

[0413]

[0414] (1) Preparation of tert-butyl 9-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate Referring to step (1) of Example 3, 350 mg of a crude product was obtained.

[0415] (2) Preparation of N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide

[0416] The crude product was prepared by referring to step (7) of Example 5 and used directly in the next step.

[0417] (3) Preparation of 3-acryloyl-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-9-carboxamide

[0418] Referring to step (8) of Example 5, 60 mg of product was prepared.

[0419] 1H-NMR(400MHz,DMSO-d6)δ:12.13(s,1H),9.91(s,1H),8.16(s,1H),7.82(d,J=8.7, 2H),7.65(d,J=8.7,2H),7.08(s,1H),6.85-6.70(m,1H),6.11-6.04(m,1H),5.66-5. 60(m,1H),3.90-3.80(m,4H),3.80-3.70(m,4H),3.57-3.44(m,4H),2.33-2.30(m,1 H),1.80-1.75(m,2H),1.66-1.45(m,6H),1.35-1.10(m,4H).LC-MS(m / z):529.4(M+H + ).

[0420] Example 7 Preparation of 9-acrylamido-N-(4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (Compound 11)

[0421]

[0422] (1) Preparation of tert-butyl 9-(benzylamino)-3-azaspiro[5.5]undecane-3-carboxylate

[0423] Dissolve tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3.7 mmol) in 10 mL of methanol, add acetic acid (1 mL), benzylamine (401 mg, 3.7 mmol) and sodium cyanoborohydride (697 mg, 11.1 mmol), react the system at 25 ° C for 2 hours, concentrate, and adjust the pH of the system to 7 with saturated sodium bicarbonate solution, extract with ethyl acetate, and concentrate the organic phase to obtain 1.5 g of a crude product.

[0424] (2) Preparation of tert-butyl 9-(dibenzylamino)-3-azaspiro[5.5]undecane-3-carboxylate

[0425] 9-(Benzylamino)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.4 g, crude product) was dissolved in DMF (20 mL), potassium carbonate (1.6 g, 11.7 mmol) and benzyl bromide (667 mg, 3.9 mmol) were added, and the system was reacted at 20°C for 2 hours, and then water was added to quench the reaction. The reaction was extracted with ethyl acetate, and the organic phase was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 6:1) to obtain 1.0 g of the product, with a two-step yield of 60.3%.

[0426] (3) Preparation of N,N-dibenzyl-3-azaspiro[5.5]undecane-9-amine

[0427] 9-(Dibenzylamino)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (990 mg, 2.2 mmol) was dissolved in ethyl acetate (5 mL), HCl / EA (5 mL) was added, and the mixture was reacted at 25°C for 30 min. After the reaction was completed, the reaction liquid was spin-dried to obtain 690 mg of the product with a yield of 90.0%.

[0428] (4) Preparation of phenyl (4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0429] 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (100 mg, 0.34 mmol), DIEA (129 mg, 1.0 mmol) and phenyl chloroformate (52 mg, 0.34 mmol) were dissolved in THF (20 mL) and reacted at 25 ° C for 1 h. After the reaction was completed, the reaction solution was spin-dried and the residue was purified by column chromatography (SiO2, MeOH:DCM=1:10) to obtain 100 mg of the product with a yield of 70.8%.

[0430] (5) Preparation of 9-(dibenzylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide

[0431] Phenyl(4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (90 mg, 0.22 mmol) was dissolved in acetonitrile (10 mL), and N,N-dibenzyl-3-azaspiro[5.5]undecane-9-amine (115 mg, 0.33 mmol) and potassium carbonate (91 mg, 0.66 mmol) were added. The mixture was reacted at 80° C. for 3 h. After the reaction was completed, the reaction solution was spin-dried and purified by column chromatography (SiO2, MeOH:DCM=1:10) to obtain 100 mg of the product with a yield of 68.0%.

[0432] (6) Preparation of 9-amino-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide

[0433] 9-(Dibenzylamino)-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (90 mg, 0.13 mmol) was dissolved in methanol (10 mL), Pd / C (90 mg) was added, and the mixture was reacted at 25 °C under a hydrogen atmosphere for 2 h. After the reaction was completed, the filtrate was collected by filtration and concentrated to obtain 100 mg of a crude product, which was directly used in the next step.

[0434] (7) Preparation of 9-acrylamido-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide

[0435] Triethylamine (77 mg, 0.60 mmol) and acryloyl chloride (18 mg, 0.20 mmol) were added to a solution of 9-amino-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (100 mg, crude product) in DMF (10 mL). The mixture was reacted at -10°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and the residue was separated by column chromatography (C18, H2O:MeOH=1:1) to obtain 30 mg of the product. 1 H-NMR(400MHz,DMSO-d6)δ:13.03(s,1H),8.62(s,1H),8.32(s,1H),7.95(d,J=7.9,1 H),7.80(d,J=8.6,2H),7.57(d,J=8.7,2H),7.32(s,1H),6.20-6.10(m,1H),6.10-5. 98(m,1H),5.70-5.55(m,1H),3.96(d,J=4.3,4H),3.81(d,J=4.3,4H),3.80-3.69(m, 4H),1.71-1.51(m,4H),1.70-1.30(m,6H),1.30-1.20(m,2H).LC-MS(M / e):544.4(M+H + ).

[0436] Example 8 Preparation of 9-acrylamido-N-(4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide (Compound 13)

[0437]

[0438] (1) Preparation of tert-butyl 9-(benzylamino)-2-azaspiro[5.5]undecane-2-carboxylate

[0439] Dissolve tert-butyl 9-oxo-2-azaspiro[5.5]undecane-2-carboxylate (1.0 g, 3.7 mmol) in 10 mL of methanol, add acetic acid (1 mL), benzylamine (401 mg, 3.7 mmol) and sodium cyanoborohydride (697 mg, 11.1 mmol), react the system at 25 ° C for 2 hours, concentrate, and adjust the pH of the system to 7 with saturated sodium bicarbonate solution. After extraction with ethyl acetate, concentrate the organic phase to obtain 1.5 g of a crude product.

[0440] (2) Preparation of tert-butyl 9-(dibenzylamino)-2-azaspiro[5.5]undecane-2-carboxylate

[0441] 9-(Benzylamino)-2-azaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (1.4 g, crude product) was dissolved in DMF (20 mL), potassium carbonate (1.6 g, 11.7 mmol) and benzyl bromide (667 mg, 3.9 mmol) were added, and the system was reacted at 20°C for 2 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 6:1) to obtain 1.0 g of the product. The two-step yield was 60.3%.

[0442] (3) Preparation of N,N-dibenzyl-2-azaspiro[5.5]undecane-9-amine

[0443] 9-(Dibenzylamino)-2-azaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (990 mg, 2.2 mmol) was dissolved in ethyl acetate (5 mL), HCl / EA (5 mL) was added, and the mixture was reacted at 25°C for 30 min. After the reaction was completed, the reaction liquid was spin-dried to obtain 690 mg of the product with a yield of 90.0%.

[0444] (4) Preparation of 9-(dibenzylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide

[0445] Phenyl(4-(4-morpholinyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (90 mg, 0.22 mmol) was dissolved in acetonitrile (10 mL), and N,N-dibenzyl-2-azaspiro[5.5]undecane-9-amine (115 mg, 0.33 mmol) and potassium carbonate (91 mg, 0.66 mmol) were added. The mixture was reacted at 80° C. for 12 h. After the reaction was completed, the reaction solution was dried and the residue was purified by column chromatography (SiO2, MeOH:DCM=1:10) to obtain 100 mg of the product with a yield of 67.9%.

[0446] (5) Preparation of 9-amino-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide

[0447] 9-(Dibenzylamino)-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide (90 mg, 0.13 mmol) was dissolved in methanol (10 mL), Pd / C (90 mg) was added, and the mixture was reacted at 25 °C under a hydrogen atmosphere for 12 h. After the reaction was completed, the filtrate was collected by filtration and concentrated to obtain 100 mg of a crude product, which was directly used in the next step.

[0448] (6) Preparation of 9-acrylamido-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide

[0449] Triethylamine (77 mg, 0.60 mmol) and acryloyl chloride (18 mg, 0.20 mmol) were added to a solution of 9-amino-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[5.5]undecane-2-carboxamide (100 mg, crude) in DMF (10 mL). The mixture was reacted at -10°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and the residue was separated by column chromatography (C18, H2O:MeOH=1:1) to obtain 10 mg of the product with a two-step yield of 13.7%.

[0450] 1 H-NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.62-8.42(m,1H),8.14(s,1H),8.01-7.87 (m,1H),7.95-7.77(m,2H),7.76-7.45(m,2H),7.01(s,1H),6.20-6.10(m,1H),6.10-5 .98(m,1H),5.70-5.55(m,1H),3.96(d,J=4.3,4H),3.81(d,J=4.3,4H),3.80-3.69(m ,4H),1.71-1.51(m,4H)1.70-1.30(m,6H),1.30-1.20(m,3H).LC-MS(M / e):544.4(M+H + ).

[0451] Example 9 Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (Compound 16)

[0452]

[0453] (1) Preparation of ethyl 2-(benzylamino)spiro[3.5]nonane-7-carboxylate

[0454] To a solution of ethyl 2-oxospiro[3.5]nonane-7-carboxylate (500 mg, 2.4 mmol) in methanol (10 mL) were added benzylamine (309 mg, 2.9 mmol), potassium acetate (709 mg, 7.2 mmol) and sodium cyanoborohydride (452 ​​mg, 7.2 mmol), and the mixture was reacted at 20 °C for 4 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with EA, and the organic phase was spin-dried to give 600 mg of a crude product.

[0455] (2) Preparation of ethyl 2-(dibenzylamino)spiro[3.5]nonane-7-carboxylate

[0456] Potassium carbonate (995 mg, 7.2 mmol) and benzyl bromide (492 mg, 2.9 mmol) were added to a solution of ethyl 2-(benzylamino)spiro[3.5]nonane-7-carboxylate (600 mg crude product) in DMF (10 mL). The mixture was reacted at 20 °C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=10:1) to obtain 450 mg of the product.

[0457] (3) Preparation of 2-(dibenzylamino)spiro[3.5]nonane-7-carboxylic acid

[0458] To a solution of ethyl 2-(dibenzylamino)spiro[3.5]nonane-7-carboxylate (450 mg, 1.1 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (440 mg, 11.0 mmol) in water (2 mL), and the mixture was reacted at 20 ° C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was diluted with water. The pH was adjusted to 3-4 with dilute hydrochloric acid, and extracted with DCM. The organic phase was spin-dried to give 400 mg of a crude product.

[0459] (4) Preparation of 2-(dibenzylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0460] To a solution of 2-(dibenzylamino)spiro[3.5]nonane-7-carboxylic acid (400 mg crude product) in DMF (10 mL) were added 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (325 mg, 1.1 mmol), HATU (836 mg, 2.2 mmol) and DIEA (426 mg, 3.3 mmol), and the mixture was reacted at 20°C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1-0:1) to give 550 mg crude product.

[0461] (5) Preparation of 2-amino-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0462] Pd / C (700 mg) was added to a solution of 2-(dibenzylamino)-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (550 mg crude product) in methanol (10 mL), and the mixture was replaced with hydrogen three times. The mixture was reacted at 40°C for 3 h. Concentrated hydrochloric acid (0.05 mL) was added to the reaction solution, and the mixture was reacted at 60°C for 12 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was spin-dried to give 300 mg of a crude product.

[0463] (6) Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0464] To a solution of 2-amino-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (150 mg crude product) in DMF (10 mL) was added cyanogen bromide (35 mg, 0.33 mmol) and potassium carbonate (137 mg, 0.99 mmol), and the mixture was reacted at 20°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=15:1, Rf~0.3) to give 40 mg of the product.

[0465] 1H-NMR (400MHz, DMSO-d6)δ:12.09(s,1H),9.87(s,1H),8.15(s,1H),7.80(d,J=8.7,2H),7.63(d,J=8.7,2H),7.07-7.02(m,1H),3.86-3.79(m, 4H),3.79-3.63(m,4H),3.61-3.50(m,1H),2.24-2.03(m,2H),2.10-1.9 0(m,1H),1.80-1.50(m,6H),1.40-1.30(m,4H).LC-MS(m / z):486.3(M+H + ).

[0466] Example 10 Preparation of 2-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide (Compound 17)

[0467]

[0468] (1) Preparation of ethyl 2-(N-methylcyanamido)spiro[3.5]nonane-7-carboxylate

[0469] Potassium carbonate (368 mg, 2.7 mmol) and cyanogen bromide (113 mg, 1.1 mmol) were added to a solution of ethyl 2-(methylamino)spiro[3.5]nonane-7-carboxylate (200 mg crude product) in CH3CN (5 mL), and the mixture was reacted at 20°C for 10 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1) to obtain 80 mg of the product.

[0470] (2) Preparation of 2-(N-methylcyanamido)spiro[3.5]nonane-7-carboxylic acid

[0471] To a solution of ethyl 2-(N-methylcyanamido)spiro[3.5]nonane-7-carboxylate (80 mg, 0.32 mmol) in methanol (5 mL) was added a solution of sodium hydroxide (128 mg, 3.2 mmol) in water (2 mL), and the reaction was carried out at 20 ° C for 3 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was diluted with water. The pH was adjusted to 3-4 with dilute hydrochloric acid (2 M), and DCM was extracted. The organic phase was spin-dried to give 60 mg of a crude product.

[0472] (3) Preparation of 2-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)spiro[3.5]nonane-7-carboxamide

[0473] To a solution of 2-(N-methylcyanamido)spiro[3.5]nonane-7-carboxylic acid (60 mg crude product) in DMF (5 mL) were added 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (80 mg, 0.27 mmol), HATU (205 mg, 0.54 mmol) and DIEA (105 mg, 0.81 mmol). The mixture was reacted at 20°C for 10 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=20:1, Rf~0.3) to give 25 mg of the product.

[0474] 1 H-NMR(400MHz,DMSO-d6)δ:12.16(s,1H),9.91(s,1H),8.16(s,1H),7.80 (d,J=8.7,2H),7.63(d,J=8.7,2H),7.08(s,1H),3.94-3.81(m,4H),3.78 -3.69(m,4H),3.50-3.45(m,1H),2.72(s,3H),2.30-2.10(m,3H),2.07-1 .90(m,2H),1.82-1.60(m,6H),1.40-1.30(m,2H).LC-MS(m / z):500.3(M+H + ).

[0475] Example 11 Preparation of 9-cyanamido-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (Compound 18)

[0476]

[0477] To a solution of 9-amino-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (70 mg, 0.14 mmol) in DMF (10 mL) were added potassium carbonate (59 mg, 0.43 mmol) and cyanogen bromide (15 mg, 0.14 mmol), and the reaction was carried out at 25 °C for 4 h. After the reaction was completed, EA and water were added to the system for extraction and separation. The organic phase was concentrated and the residue was purified by preparative plate (DCM / MeOH / HOAc=20 / 1 / 0.05) to obtain 30 mg of the product with a yield of 41.6%.

[0478] 1H-NMR (400MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 4.36Hz, 2H), 7.51 (d, J = 4.32Hz, 2H), 7.02 (s, 1H), 6.77-6.74 (m, 1H),3.90-3.80(m,4H),3.80-3.70(m,4H),3.50-3.40(m,4H),3.05-2.9 5(m,1H),1.71-1.61(m,4H),1.50-1.10(m,8H).LC-MS(M / e):515.3(M+H + ).

[0479] Example 12 Preparation of 9-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (Compound 19)

[0480]

[0481] (1) Preparation of tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate

[0482] Methylamine hydrochloride (809 mg, 12.0 mmol), potassium acetate (2.9 g, 29.5 mmol) and sodium cyanoborohydride (1.9 g, 30.3 mmol) were added to a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (2.67 g, 10.0 mmol) in methanol (40 mL). The mixture was reacted at 25°C for 16 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated, EA was added and the mixture was extracted with water. The organic phase was concentrated to obtain the product (2.3 g, yield 81.8%).

[0483] (2) Preparation of tert-butyl 9-(((benzyloxy)carbonyl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate

[0484] DIEA (2.8 g, 21.7 mmol) and CbzCl (1.4 g, 8.2 mmol) were added to a solution of tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 7.1 mmol) in DCM (30 mL), and the mixture was reacted at 25° C. for 2 h. The reaction was completed. DCM and water were added to the system for extraction and separation, and the organic phase was concentrated and chromatographed on a silica gel column (PE / EA=10 / 1) to obtain the product (2.1 g, yield 71.0%).

[0485] (3) Preparation of benzylmethyl (3-azaspiro [5.5] undecane-9-yl) carbamate hydrochloride

[0486] 4M HCl EA solution (10 mL) was added to tert-butyl 9-(((benzyloxy)carbonyl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (600 mg, 1.4 mmol) and reacted at 25° C. for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain the product (450 mg, yield 91.9%).

[0487] (4) Preparation of benzylmethyl (3-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-3-azaspiro[5.5]undecane-9-yl)carbamate

[0488] 4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (300 mg crude product) and potassium carbonate (415 mg, 3.0 mmol) were added to benzylmethyl(3-azaspiro[5.5]undecane-9-yl)carbamate hydrochloride (353 mg, 1.0 mmol) in DMF (15 mL), and the mixture was reacted at 85°C for 12 h. The reaction was completed. EA and water were added to the system for extraction and separation, and the organic phase was concentrated and purified by C18 reverse phase (water / methanol=4 / 6) to obtain the product (250 mg, yield 39.2%).

[0489] (5) Preparation of 9-(methylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide

[0490] Pd / C (100 mg) was added to benzylmethyl (3-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-3-azaspiro[5.5]undec-9-yl)carbamate (200 mg, 0.31 mmol) in methanol (15 mL). The mixture was reacted at 25°C for 6 h under a hydrogen atmosphere. The reaction was completed. The system was filtered under reduced pressure through diatomaceous earth, the filter cake was washed with (DCM / MeOH=10 / 1), and the filtrate was concentrated to obtain the product (65 mg, yield 41.6%).

[0491] (6) Preparation of 9-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide

[0492] Potassium carbonate (51 mg, 0.37 mmol) and cyanogen bromide (13 mg, 0.12 mmol) were added to a solution of 9-amino-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-3-azaspiro[5.5]undecane-3-carboxamide (70 mg, 0.14 mmol) in DMF (8 mL), and the mixture was reacted at 25 °C for 3 h. After the reaction was completed, EA and water were added to the system for extraction and separation. The organic phase was concentrated and the residue was purified by preparative plate (DCM / MeOH=20 / 1) to obtain 50 mg of the product with a yield of 67.6%.

[0493] 1 H-NMR (400MHz, DMSO-d6)δ:8.51(s,1H),8.15(s,1H),7.75(d,J=4.24Hz,2H),7.51(d,J=4.16Hz,2H),7.02(s,1H),3.87-3.82( m,4H),3.78-3.73(m,4H),3.53-3.45(m,4H),2.85-2.75(m,4H),1.77-1.68(m,4H),1.50-1.10(m,8H).LC-MS(M / e):529.4(M+H + ).

[0494] Example 13 Preparation of 2-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxamide (Compound 21)

[0495]

[0496] (1) Preparation of tert-butyl 2-((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate

[0497] To a solution of tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 0.42 mmol) in DCM (5 mL) was added benzyl chloroformate (86 mg, 0.50 mmol) and DIEA (163 mg, 1.3 mmol) at 0°C. The mixture was reacted for 2 h at 0°C. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=3:1) to give 100 mg of the product in a yield of 64.2%.

[0498] (2) Preparation of tert-butyl 2-((benzyloxy)carbonyl)(methyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate

[0499] To a solution of tert-butyl 2-((benzyloxy)carbonyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 0.27 mmol) in DMF (3 mL) was added sodium hydrogen sulfide (60%, 22 mg, 0.55 mmol) at 0°C, and the reaction was carried out at 0°C for 0.5 h. Methyl iodide (46 mg, 0.32 mmol) was added, and the reaction was carried out at 20°C for 1 h. LC-MS showed that the reaction was completed. The reaction solution was diluted with water, extracted with EA, and the organic phase was spin-dried. The residue was separated by column chromatography (SiO2, PE:EA=3:1) to obtain 100 mg of the product with a yield of 96.4%.

[0500] (3) Preparation of benzylmethyl (7-azaspiro[3.5]nonan-2-yl)carbamate

[0501] To a solution of tert-butyl 2-((benzyloxy)carbonyl)(methyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 0.26 mmol) in methanol (3 mL) was added hydrochloric acid / dioxane (4 M, 10 mL) and the mixture was reacted at 20 °C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to give 70 mg of a crude product.

[0502] (4) Preparation of benzylmethyl (7-((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-7-azaspiro[3.5]nonan-2-yl)carbamate

[0503] To a solution of phenyl(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)carbamate (100 mg, 0.24 mmol) in DMF (5 mL) were added benzylmethyl(7-azaspiro[3.5]nonan-2-yl)carbamate (70 mg crude product) and potassium carbonate (100 mg, 0.72 mmol), and the mixture was reacted at 80 °C for 14 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by reverse phase column chromatography (C18, H2O:MeOH=80:20-50:50) to give 80 mg of the product in a yield of 54.5%.

[0504] (5) Preparation of 2-(methylamino)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxamide

[0505] Pd / C (80 mg) was added to a solution of benzylmethyl (7-((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (80 mg, 0.13 mmol) in methanol (5 mL), and the mixture was replaced with hydrogen three times. The mixture was reacted at 20°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was filtered and the filtrate was dried to give 60 mg of a crude product.

[0506] (6) Preparation of 2-(N-methylcyanamido)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxamide

[0507] To a solution of 2-(methylamino)-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxamide (60 mg crude product) in DMF (5 mL) were added cyanogen bromide (14 mg, 0.13 mmol) and potassium carbonate (54 mg, 0.39 mmol). The mixture was reacted at 20°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=15:1, Rf~0.3) to give 20 mg of the product.

[0508] 1 H-NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.55(s,1H),8.14(s,1H),7.75 (d,J=8.8,2H),7.50(d,J=8.8,2H),7.02(s,1H),3.87-3.82(m,4H),3.76 -3.63(m,4H),3.62-3.48(m,1H),3.41-3.30(m,4H),2.73(s,3H),2.20-2 .09(m,2H),1.78-1.69(m,2H),1.59-1.43(m,4H).LC-MS(m / z):501.3(M+H + ).

[0509] Example 14 Preparation of 2-acryloyl-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (Compound 22)

[0510]

[0511] Triethylamine (34 mg, 0.34 mmol) was added to a solution of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (30 mg, 0.067 mmol) in THF (10 ml), the temperature was cooled to -10°C, acryloyl chloride (9.5 mg, 0.10 mmol) was added, and the mixture was reacted at 0°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to obtain a crude product, which was separated by a normal phase column (SiO2, DCM:MeOH=90:10) to obtain 14 mg of the product, with a yield of 42%.

[0512] 1 H-NMR (400MHz, DMSO-d6) δ: 12.10 (s, 1H), 9.90 (s, 1H), 8.15 (s, 1H), 7.82-7.80 (d, J = 8. 7,2H),7.65-7.62(d,J=8.7,2H),7.07(s,1H),6.32-6.26(m,1H),6.10-6.09(m,1H),5.6 5(m,1H),3.92(m,1H),3.87-3.84(m,5H),3.74-3.72(m,4H),3.63(m,1H),3.55(m,1H), 2.33-2.30(m,1H),1.99(m,2H),1.74(m,2H),1.48-1.43(m,4H).LC-MS(m / z):501.3(M+H + ).

[0513] Example 15 Preparation of 2-acetyl-N-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (Compound 23)

[0514]

[0515] To a solution of DCM (3 ml) and DMF (3 mL) of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (30 mg crude product) at 0°C, DIEA (26 mg, 0.20 mmol) and acetyl chloride (6 mg, 0.076 mmol) were added. The mixture was reacted at 0°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=10:1, Rf~0.3) to give 25 mg.

[0516] 1H-NMR (400MHz, DMSO-d6) δ: 12.10 (s, 1H), 9.90 (d, J = 9.8, 1H), 8.15 (s, 1H), 7.80 (d, J = 8.8, 2H), 7.63 (d, J = 8.8, 2H), 7.06 (s, 1H), 4.00 -3.60(m,10H),3.60-3.40(m,2H),2.30-2.20(m,1H),1.90-1.81(m,2H),1.80-1.60(m,5H),1.50-1.30(m,4H).LC-MS(m / z):489.3(M+H) + ).

[0517] Example 16 Preparation of 2-cyano-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.3]heptane-6-carboxamide (Compound 26)

[0518]

[0519] To a solution of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.3]heptane-6-carboxamide (100 mg, 0.24 mmol) in DMF (10 ml) at 20°C, potassium carbonate (91 mg, 0.66 mmol) and bromonitrile (26 mg, 0.24 mmol) were added. The mixture was reacted at 20°C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, and a solid precipitated. The crude product was filtered and separated using a normal phase column (SiO2, DCM:MeOH=90:10) to obtain 4 mg of the product. The yield was 3.8%.

[0520] 1 H-NMR (400MHz, DMSO-d6)δ:12.10(s,1H),9.90(s,1H),8.15(s,1H),7.82-7.79(d,J=8.7,2H),7.63-7.61(d,J=8.7,2H) ,7.06-7.05(s,1H),4.42-4.05(m,4H),3.88-3.74(m,8H),3.18-2.90(m,1H),1.99-1.80(m,4H).LC-MS(m / z):444.3(M+H + ).

[0521] Example 17 Preparation of N-(2-cyano-2-azaspiro[3.5]nonan-7-yl)-4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzamide (Compound 32)

[0522]

[0523] (1) Preparation of 4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoic acid

[0524] At 20°C, 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (2.0 g, 6.1 mmol) was dissolved in DMA (40 ml) and H2O (10 ml), and 4-phenylboronic acid (1.5 g, 9.0 mmol), Pd(dppf)Cl2 (440 mg, 0.61 mmol) and K2CO3 (1.7 g, 12.2 mmol) were added. The reaction was carried out at 120°C for 7 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, and a solid was precipitated. The crude product was filtered and washed with water three times to obtain 600 mg of the product. The yield was 30.3%.

[0525] (2) Preparation of tert-butyl 7-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzamido)-2-azaspiro[3.5]nonane-2-carboxylate

[0526] At 20°C, 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoic acid (500 mg, 1.5 mmol) was dissolved in DMF (10 ml), and tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (400 mg, 1.7 mmol), HATU (874 mg, 2.3 mmol) and TEA (455 mg, 4.5 mmol) were added. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, and a solid was precipitated. The product was filtered to obtain 800 mg, with a yield of 94.9%.

[0527] (3) Preparation of 4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-N-(2-azaspiro[3.5]nonan-7-yl)benzamide

[0528] At 20°C, tert-butyl 7-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzamido)-2-azaspiro[3.5]nonane-2-carboxylate (800 mg, 1.5 mmol) was dissolved in dioxane (5 ml), dioxane hydrochloride (5 mL) was added, and the mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried by spin drying to obtain 600 mg of the product. The yield was 91.8%.

[0529] (4) Preparation of N-(2-cyano-2-azaspiro[3.5]nonan-7-yl)-4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzamide

[0530] At 20°C, 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-N-(2-azaspiro[3.5]nonan-7-yl)benzamide (100 mg, 0.22 mmol) was dissolved in DMF (5 ml), K2CO3 (207 mg, 1.5 mmol) was added, CNBr (21 mg, 0.20 mmol) was dissolved in DMF, and 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 16.0 mg of the product with a yield of 15.5%.

[0531] 1 H-NMR(400MHz,DMSO-d6)δ:12.28(s,1H),8.18(s,1H),8.15-8.13(m,1H) ,7.97-7.95(d,J=8.4,2H),7.87-7.85(d,J=8.4,2H),7.29(s,1H),3.89- 3.87(m,6H),3.79(s,2H),3.74-3.72(m,5H),1.99-1.96(m,2H),1.74-1. 71(m,2H),1.50-1.46(m,2H),1.32-1.21(m,2H).LC-MS(m / z):472.2(M+H + ).

[0532] Example 18 Preparation of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-propionyl-2-azaspiro[3.5]nonane-7-carboxamide (Compound 33)

[0533]

[0534] To a solution of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (100 mg, 0.22 mmol) in DMAc (10 ml), HATU (125 mg, 0.33 mmol) and DIEA (43 mg, 0.33 mmol) were added at 0°C. Propylic acid (23 mg, 0.33 mmol) was added and the reaction was carried out for 1 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to obtain a crude product, which was separated using a normal phase column (SiO2, DCM:MeOH=90:10) to obtain 10 mg of the product. Yield: 9.1%.

[0535] 1H-NMR(400MHz,DMSO-d6)δ:12.10(s,1H),9.90(s,1H),8.15(s,1H),7.82-7.80 (d,J=8.7,2H),7.64-7.62(d,J=8.7,2H),7.06(s,1H),4.40-4.39(d,1H),3.87- 3.84(m,5H),3.78(m,1H),3.73-3.71(m,4H),3.62(m,1H),3.54(m,1H),2.33-2. 30(m,1H),1.99(m,2H),1.74(m,2H),1.48-1.43(m,4H).LC-MS(m / z):499.3(M+H + ).

[0536] Example 19 Preparation of 7-(2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetyl)-2,7-diazaspiro[3.5]nonane-2-carbonitrile (Compound 35)

[0537]

[0538] (1) Preparation of 2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetic acid

[0539] At 20°C, 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (2.0 g, 6.1 mmol) was dissolved in dioxane (40 ml) and H2O (10 ml), and 4-(carboxymethyl)phenylboronic acid (1.7 g, 9.4 mmol), Pd(dppf)Cl2 (440 mg, 0.61 mmol) and K2CO3 (1.7 g, 12.2 mmol) were added. The mixture was reacted at 100°C for 7 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water, and a solid was precipitated. The crude product was filtered and washed with water three times to obtain 500 mg of the product. The yield was 24.3%.

[0540] (2) Preparation of tert-butyl 7-(2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0541] 200 mg of product was prepared by the method of step (1) of reference example 3 with a yield of 24.4%.

[0542] (3) Preparation of 2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-1-(2,7-diazaspiro[3.5]nonan-7-yl)ethan-1-one

[0543] At 20°C, tert-butyl 7-(2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.37 mmol) was dissolved in dioxane (5 ml), and dioxane hydrochloride solution (5 mL) was added. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried to give 150 mg of the product. The yield was 90.9%.

[0544] (5) Preparation of 7-(2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetyl)-2,7-diazaspiro[3.5]nonane-2-carbonitrile

[0545] At 20°C, 2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-1-(2,7-diazaspiro[3.5]non-7-yl)ethan-1-one (70 mg, 0.16 mmol) was dissolved in DMF (5 ml), K2CO3 (207 mg, 1.5 mmol) was added, CNBr (21 mg, 0.20 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 purified by thin layer chromatography (DCM:MeOH=10:1) to give 16.0 mg of the product with a yield of 21.2%.

[0546] 1 H-NMR(400MHz,DMSO-d6)δ:12.16(s,1H),8.16(s,1H),7.82(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H),7.12( s,1H),3.89-3.87(m,8H),3.74-3.72(m,6H),3.67-3.54(m,4H),1.74-1.71(m,4H).LC-MS(m / z):472.2(M+H + ).

[0547] Example 20 Preparation of 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-N-(2-propionyl-2-azaspiro[3.5]nonan-7-yl)benzamide (Compound 36)

[0548]

[0549] HATU (125 mg, 0.33 mmol) and DIEA (43 mg, 0.33 mmol) were added to 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-N-(2-azaspiro[3.5]non-7-yl)benzamide (100 mg, 0.22 mmol) in DMAc (10 ml). Propylic acid (23 mg, 0.33 mmol) was added at 0°C and reacted for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried to obtain a crude product, which was separated by a normal phase column (SiO2, DCM:MeOH=90:10) to obtain 3.6 mg of the product, with a yield of 3.3%.

[0550] 1 H-NMR(400MHz,DMSO-d6)δ:12.29(s,1H),8.18-8.17(m,2H),7.98-7.96(d ,J=8.7,2H),7.89-7.87(d,J=8.7,2H),7.29(s,1H),4.40-4.39(d,1H),3.9 0-3.87(m,5H),3.80-3.71(m,6H),3.64(m,1H),3.56(m,1H),1.99(m,2H), 1.74(m,2H),1.54-1.51(m,2H),1.37-1.34(m,2H).LC-MS(m / z):499.3(M+H + ).

[0551] Example 21 Preparation of N-methyl-N-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-propionyl-2-azaspiro[3.5]nonane-7-carboxamide (Compound 38)

[0552]

[0553] (1) Preparation of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0554] To a solution of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.8 mmol) in DMF (10 mL) was added NaH (60%, 216 mg, 5.4 mmol) at 0°C, and the mixture was reacted for 0.5 h at 0°C. SEM-Cl (450 mg, 2.7 mmol) was added and the mixture was reacted for 1 h at 0°C. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=3:1) to give 700 mg of the product with a yield of 95.5%.

[0555] (2) Preparation of 4-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0556] Morpholine (370 mg, 4.2 mmol) was added to a solution of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (700 mg, 1.7 mmol) in n-butanol (10 mL). The mixture was reacted at 100 °C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1) to give 700 mg of the product in a yield of 89.0%.

[0557] (3) Preparation of 4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline

[0558] Potassium carbonate (1.0 g, 7.2 mmol) was added to a solution of (4-aminophenyl)borate hydrochloride (390 mg, 2.8 mmol) in dioxane (15 mL) and water (3 mL), and the mixture was stirred at 30 °C for 5 min. Pd(dppf)Cl2 (110 mg, 0.15 mmol) and 4-(6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (700 mg, 1.5 mmol) were added. The mixture was replaced with nitrogen three times and the reaction was carried out at 100 °C for 10 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1) to give 500 mg of the product with a yield of 77.3%.

[0559] (4) Preparation of tert-butyl 7-((4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0560] To a solution of 4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (300 mg, 0.70 mmol) in DMF (5 mL) were added HATU (798 mg, 2.1 mmol), 2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (226 mg, 0.84 mmol) and DIEA (271 mg, 2.1 mmol), and the mixture was reacted at 30° C. for 2 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1) to give 400 mg of the product in a yield of 83.8%.

[0561] (5) Preparation of tert-butyl 7-(methyl(4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0562] To a solution of tert-butyl 7-((4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate (400 mg, 0.59 mmol) in DMF (5 mL) was added NaH (60%, 47 mg, 1.2 mmol) at 0°C, and the mixture was reacted for 0.5 h at 0°C. Methyl iodide (92 mg, 0.65 mmol) was then added, and the mixture was reacted for 1 h at 0°C. LC-MS showed that the reaction was complete, and the reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by column chromatography (SiO2, PE:EA=1:1) to give 300 mg of the product with a yield of 73.5%.

[0563] (6) Preparation of N-methyl-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide

[0564] To a solution of tert-butyl 7-(methyl(4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 0.43 mmol) in DCM (10 mL) was added TFA (3 mL), and the mixture was reacted at 30 ° C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried, and the residue was dissolved in acetonitrile (5 mL). Ammonia water (5 mL) was added, and the mixture was reacted at 30 ° C for 16 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with DCM, and the organic phase was spin-dried to give 200 mg of a crude product.

[0565] (7) Preparation of N-methyl-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-propionyl-2-azaspiro[3.5]nonane-7-carboxamide

[0566] To a solution of N-methyl-N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (100 mg crude product) in DMF (5 mL) were added HATU (167 mg, 0.44 mmol), propiolic acid (15 mg, 0.21 mmol) and DIEA (57 mg, 0.44 mmol), and the mixture was reacted at 25°C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=12:1, Rf~0.4) to give 15 mg of the product.

[0567] 1 H-NMR(400MHz,DMSO-d6)δ:12.27(s,1H),8.18(s,1H),7.96(d,J=8.0,2H),7.37 (d,J=8.0,2H),7.24(s,1H),4.45-4.30(m,1H),3.92-3.82(m,4H),3.80-3.75(m, 1H),3.75-3.70(m,4H),3.68-3.50(m,4H),3.50-3.35(m,2H),2.20-2.12(m,1H), 1.80-1.70(m,2H),1.65-1.55(m,2H),1.50-1.40(m,4H).LC-MS(m / z):513.3(M+H + ).

[0568] Example 22 Preparation of N-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-(vinylsulfonyl)-2-azaspiro[3.5]nonane-7-carboxamide (Compound 46)

[0569]

[0570] To a solution of N-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-azaspiro[3.5]nonane-7-carboxamide (100 mg, 0.22 mmol) in NMP (5 mL) were added sodium tert-butoxide (42 mg, 0.44 mmol) and ethylenesulfonyl chloride (56 mg, 0.44 mmol), and the mixture was reacted at 30 °C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=12:1, Rf~0.5) to give 10 mg of the product with a yield of 8.3%.

[0571] 1 H-NMR(400MHz,DMSO-d6)δ:12.11(s,1H),9.90(s,1H),8.14(s,1H),7.80(d,J=8.8,2H ),7.62(d,J=8.8,2H),7.10-7.00(m,2H),6.27(d,J=10.0,1H),6.16(d,J=16.4,1H),3. 92-3.80(m,4H),3.80-3.70(m,4H),3.65-3.55(m,2H),3.50-3.40(m,2H),2.30-2.18(m ,1H),1.90-1.80(m,2H),1.75-1.62(m,2H),1.50-1.35(m,4H).LC-MS(m / z):537.3(M+H + ).

[0572] Example 23 Preparation of 7-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carbonitrile (Compound 47)

[0573]

[0574] (1) Preparation of 2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)ethan-1-ol

[0575] At 25°C, 2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetic acid (500 mg, 1.5 mmol) was dissolved in tetrahydrofuran (20 ml), lithium aluminum tetrahydride (342 mg, 9.0 mmol) was added, and the mixture was reacted at 25°C for 3 h. LC-MS showed that the reaction was complete. Water was added to quench the reaction, and the reaction solution was spin-dried and subjected to column chromatography (SiO2, DCM:MeOH=10:1) to obtain 300 mg of the product. The yield was 61.7%.

[0576] (2) Preparation of 2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetaldehyde

[0577] 2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)ethane-1-ol (300 mg, 0.93 mmol) was dissolved in DCM (20 ml) at 25°C, and Dess-Martin periodinane (1.2 g, 2.8 mmol) was added. The reaction was carried out at 25°C for 3 h. LC-MS showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was spin-dried and purified by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 250 mg of the product. The yield was 83.5%.

[0578] (3) Preparation of tert-butyl 7-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0579] At 25°C, 2-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acetaldehyde (250 mg, 0.78 mmol) was dissolved in methanol (10 ml), and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (271 mg, 1.2 mmol), sodium cyanoborohydride (245 mg, 3.9 mmol) and glacial acetic acid (0.1 mL) were added. The mixture was reacted at 25°C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and purified by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 90 mg of the product. The yield was 21.7%.

[0580] (4) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0581] At 25°C, tert-butyl 7-(4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (90 mg, 0.17 mmol) was dissolved in dioxane (5 ml), and dioxane hydrochloride solution (5 mL) was added. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried to obtain 60 mg of the product with a yield of 81.6%.

[0582] (5) Preparation of 7-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carbonitrile

[0583] At 25°C, 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (60 mg, 0.14 mmol) was dissolved in DMF (5 ml), K2CO3 (207 mg, 1.5 mmol) was added, CNBr (21 mg, 0.20 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 purified by thin layer chromatography (DCM:MeOH=10:1) to give 10.0 mg of the product in a yield of 15.6%.

[0584] 1 H-NMR (400MHz, DMSO-d6) δ: 12.16 (s, 1H), 8.16 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.4Hz, 2H), 7.12 (s, 1H), 3.89-3.87 (m, 8H), 3. 74-3.72(m,4H),3.51-3.40(m,2H),3.35-3.20(m,2H),2.79-2.61(m,2H),2.51-2.43(m,2H),1.74-1.71(m,4H).LC-MS(m / z):458.3(M+H) + ).

[0585] Example 24 Preparation of 7-(((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)amino)methyl)-2-azaspiro[3.5]nonane-2-carbonitrile (Compound 48)

[0586]

[0587] (1) Preparation of tert-butyl 7-(((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)amino)methyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0588] At 25°C, tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.39 mmol) was dissolved in methanol (2 ml) and dichloromethane (1 ml), and 4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (126 mg, 0.43 mmol), NaBH3CN (74 mg, 1.2 mmol) and glacial acetic acid (0.1 ml) were added. The mixture was reacted at 25°C for 1 h. LC-MS showed that the reaction was complete. Water was added to quench the reaction. The reaction solution was spin-dried and the product was obtained by column chromatography (C18, H2O:ACN=1:2) with a yield of 47.6%.

[0589] (2) Preparation of N-((2-azaspiro[3.5]non-7-yl)methyl)-4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline

[0590] At 25°C, tert-butyl 7-(((4-(4-morpholine-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)amino)methyl)-2-azaspiro[3.5]nonane-2-carboxylate (80 mg, 0.15 mmol) was dissolved in MeOH (1 ml), 4 M HCl (1 mL) was added, and the mixture was reacted at 25°C for 1 h. The organic phase was spin-dried to obtain 60 mg of the product, with a yield of 92.3%.

[0591] (3) Preparation of 7-(((4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)amino)methyl)-2-azaspiro[3.5]nonane-2-carbonitrile

[0592] At 25°C, N-((2-azaspiro[3.5]non-7-yl)methyl)-4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (20 mg, 0.046 mmol) was dissolved in DMF (2 ml), potassium carbonate (44 mg, 0.32 mmol) and cyanogen bromide (7 mg, 0.069 mmol) were added at 0°C, and the reaction was carried out at 0°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried and climbed on a plate (SiO2, DCM:MeOH=20:1) to obtain 2 mg of the product, with a yield of 9.5%. 1 H-NMR (400MHz, DMSO-d6) δ: 12.16 (s, 1H), 8.10 (s, 1H), 7.59-7.57 (d, J = 8.2, 2H), 6. 82(s,1H),6.58-6.55(d,J=8.2,2H),5.89-5.88(m,1H),3.83-3.81(m,5H),3.75-3. 71(m,5H),3.39-3.37(m,2H),2.85-2.84(m,2H),1.95-1.84(m,2H),1.73-1.64(m,2 H),1.56-1.43(m,1H),1.38-1.25(m,2H),0.98-0.85(m,2H).LC-MS(m / z):458.3(M+H + ).

[0593] Example 25 Preparation of 1-(7-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 52)

[0594]

[0595] At 20°C, 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (50 mg, 0.12 mmol) was dissolved in DMF (5 ml), triethylamine (36 mg, 0.36 mmol) was added, acryloyl chloride (12 mg, 0.13 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 10 mg, with a yield of 17.1%.

[0596] 1 H-NMR(400MHz,DMSO-d6)δ:12.14(s,1H),8.15(s,1H),7.79(d,J=8.12Hz,2H),7.79( d,J=8.16Hz,2H),7.10(s,1H),6.41-6.20(m,1H),6.05(d,J=19.24Hz,1H),5.63(d,J= 12.52Hz,1H),3.89-3.87(m,8H),3.74-3.72(m,4H),3.51-3.40(m,2H),3.35-3.20(m, 2H),2.79-2.61(m,2H),2.51-2.43(m,2H),1.74-1.71(m,4H).LC-MS(m / z):487.3(M+H + ).

[0597] Example 26 Preparation of 1-(7-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-yn-1-one (Compound 53)

[0598]

[0599] 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (50 mg, 0.12 mmol) was dissolved in DMF (5 ml) at 20°C, and DIEA (77 mg, 0.60 mmol), propiolic acid (13 mg, 0.18 mmol) and HATU (137 mg, 0.36 mmol) were added. The reaction was carried out at 25°C for 1 h. LC-MS showed that the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was spin-dried and dried on a plate (DCM:MeOH=10:1) to obtain 2 mg of the product. The yield was 3.4%.

[0600] 1 H-NMR (400MHz, DMSO-d6)δ:12.14(s,1H),8.15(s,1H),7.79(d,J=8.12Hz,2H),7.79(d,J=8.16Hz,2H),7.10(s,1H),4.40(s,1H),3.89-3.87(m, 8H),3.74-3.72(m,4H),3.51-3.40(m,2H),3.35-3.20(m,2H),2.79-2.6 1(m,2H),2.51-2.43(m,2H),1.74-1.71(m,4H).LC-MS(m / z):485.3(M+H + ).

[0601] Example 27 Preparation of 1-(7-(4-(4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 56)

[0602]

[0603] (1) Preparation of 4-(4,4-difluoropiperidin-1-yl)-6-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0604] 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 5.0 mmol) was dissolved in DMSO (15 ml), DIEA (1.3 g, 10 mmol) and 4,4-difluoropiperidine (605 mg, 5.0 mmol) were added, and the mixture was reacted at 80°C for 16 h. LC-MS showed that the reaction was complete. 50 ml of water was added, and a solid was precipitated. The product (2.1 g) was obtained by filtration.

[0605] (2) Preparation of tert-butyl 7-(4-(4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0606] 4-(4,4-Difluoropiperidin-1-yl)-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (364 mg, 1.0 mmol) was dissolved in dioxane (20 ml), and 2 ml of water, tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (456 mg, 1.0 mmol), sodium carbonate (212 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol) were added. Nitrogen was replaced three times, and the reaction was carried out at 100° C. for 16 h. LC-MS showed that the reaction was complete. The product was filtered and the filtrate was dried to give a crude product. Column chromatography (PE:EA=2:8) gave 230 mg of the product in a yield of 40.6%.

[0607] (3) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0608] Dissolve tert-butyl 7-(4-(4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.35 mmol) in dioxane (10 ml), add dioxane hydrochloride (4 M) solution (10 ml), react at 20° C. for 1 h, LC-MS shows the reaction is complete, spin dry to obtain 160 mg of the product.

[0609] (4) Preparation of 1-(7-(4-(4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0610] To a solution of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(4,4-difluoropiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.3 mmol) in DMAc (5 ml), DIEA (78 mg, 0.6 mmol) was added, the temperature was lowered to 0°C, acryloyl chloride (32 mg, 0.36 mmol) was added, the mixture was reacted at 0°C for 1 h, LC-MS showed the reaction was complete, water (20 ml) was added to quench the reaction, a solid was precipitated, the crude product was filtered, and separated using a normal phase column (SiO2, DCM:MeOH=90:10) to give 17 mg of the product, with a yield of 10.9%.

[0611] 1H-NMR(400MHz,DMSO-d6)δ:12.20(s,1H),8.19(s,1H),7.83-7.81(d,J=8.12Hz,2H ),7.29-7.26(d,J=8.16Hz,2H),7.12(s,1H),6.33-6.27(m,1H),6.10-6.09(m,1H) ,5.65-5.62(m,1H),4.03-4.02(m,4H),3.87(m,2H),3.58(m,2H),2.76-2.74(m,2H ),2.37-2.32(m,4H),2.11-1.96(m,6H),1.76-1.71(m,4H).LC-MS(m / z):521.3(M+H + ).

[0612] Example 28 Preparation of 1-(7-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 57)

[0613]

[0614] (1) Preparation of 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide

[0615] At 25°C, 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 3.6 mmol) was dissolved in DMSO (20 ml), and thiomorpholine 1,1-dioxide (584 mg, 4.3 mmol) and DIEA (1.4 g, 10.8 mmol) were added. The mixture was reacted at 100°C for 16 h. LC-MS showed that the reaction was complete. The mixture was extracted with EA and slurried to obtain 400 mg of the product with a yield of 29.4%.

[0616] (2) Preparation of tert-butyl 7-(4-(4-(1,1-dioxodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0617] At 25°C, 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (400 mg, 1.1 mmol) was dissolved in 1,4-dioxane (20 ml) and water (5 ml), and tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (730 mg, 1.6 mmol), K2CO3 (455 mg, 3.3 mmol) and Pd(dppf)Cl2 (80 mg, 0.11 mmol) were added. The mixture was reacted at 80°C for 2 h. The organic phase was spin-dried and passed through a silica gel column (DCM:MeOH=20:1) to obtain 250 mg of the product. The yield was 39.2%.

[0618] (3) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide

[0619] At 25°C, tert-butyl 7-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (250 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 ml), HCl (10 mL) was added, and the mixture was reacted at 25°C for 1 h. The mixture was dried by rotation, and LC-MS showed that the reaction was completed. The product was dried by rotation to obtain 185 mg, with a yield of 89.5%.

[0620] (4) Preparation of 1-(7-(4-(4-(1,1-dioxodimoroyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0621] At 25°C, 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (40 mg, 0.083 mmol) was dissolved in DMF (10 ml). DIEA (32 mg, 0.25 mmol) and acryloyl chloride (8 mg, 0.083 mmol) were added at 0°C. The mixture was reacted at 0°C for 0.5 h. LC-MS showed that the reaction was complete. The mixture was extracted with EA, and the reaction solution was spin-dried. The product (4 mg) was obtained by climbing a large plate (SiO2, DCM:MeOH=15:1). The yield was 9.1%.

[0622] 1H-NMR(400MHz,DMSO-d6)δ:12.28(s,1H),8.22(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,2H),3.57-3.54(m,2H),3.47-3.44(m,2H),3.29-3.22 (m,4H),2.75-2.71(m,2H),2.39-2.33(m,4H),1.73-1.64(m,4H).LC-MS(m / z):535.2(M+H + ).

[0623] Example 29 Preparation of 1-(7-(4-(4-(-4-hydroxypiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 58)

[0624]

[0625] (1) Preparation of tert-butyl 4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carboxylate

[0626] At 20°C, tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 9.9 mmol) was dissolved in tetrahydrofuran (50 ml), and tert-butyldiphenylsilyl chloride (4.0 g, 15.0 mmol) and imidazole (2.1 g, 30.0 mmol) were added. The mixture was reacted at 25°C for 4 h. LC-MS showed that the reaction was complete. The reaction liquid was dried by spin drying, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1) to obtain 1.0 g of the product, with a yield of 22.8%.

[0627] (2) Preparation of 4-((tert-butyldiphenylsilyl)oxy)piperidine

[0628] To a solution of tert-butyl 4-((tert-butyldiphenylsilyl)oxy)piperidine-1-carboxylate (1.0 g, 2.3 mmol) in ethyl acetate (20 mL) was added hydrogen chloride-ethyl acetate solution (10 mL), and the mixture was reacted at 25° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was spin-dried to obtain 500 mg of a crude product, which was directly used in the next step.

[0629] (3) Preparation of 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-6-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0630] 4-((tert-butyldiphenylsilyl)oxy)piperidine (500 mg, crude product) was added to a solution of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.72 mmol) in n-butanol (20 mL). The mixture was reacted at 100°C for 6 hours. LCMS showed that a product was generated. The reaction solution was spin-dried and the residue was purified by column chromatography (SiO2, dichloromethane: methanol = 10:1) to obtain 400 mg of the product with a yield of 95.4%.

[0631] (4) Preparation of tert-butyl 7-(4-(4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0632] To a solution of 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 0.69 mmol) in 1,4-dioxane (40 mL) were added tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (456 mg, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 0.070 mmol), sodium carbonate (286 mg, 2.7 mmol) and water (8 mL). The mixture was reacted at 80° C. for 6 hours under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction solution was spin-dried and purified by column chromatography (SiO2, dichloromethane:methanol=10:1) to obtain 400 mg of the product with a yield of 73.9%.

[0633] (5) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0634] To a solution of tert-butyl 7-(4-(4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.13 mmol) in 1,4-dioxane (10 mL), add hydrogen chloride-dioxane solution (5 mL) and react at 25° C. for 1 hour. LCMS showed that the reaction was complete, and the reaction solution was spin-dried to obtain 100 mg of crude product, which was directly used in the next step.

[0635] (6) Preparation of 1-(7-(4-(4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0636] Triethylamine (101 mg, 1.0 mmol) and acryloyl chloride (13 mg, 0.14 mmol) were added to a DMF (15 mL) solution of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, crude product). The mixture was reacted at -10°C for 30 minutes. LCMS showed that a product was generated. The reaction was quenched by adding water. Solids precipitated. The solids were filtered, collected, and dried to obtain 100 mg of crude product, which was directly used in the next step.

[0637] (7) Preparation of 1-(7-(4-(4-(-4-hydroxypiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0638] 1-(7-(4-(4-(4-(((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (100 mg, crude product) was dissolved in concentrated hydrochloric acid (5 mL) and reacted at 25° C. for 5 hours. LCMS showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected and separated on a preparative plate (dichloromethane:methanol=10:1) to obtain 10 mg of the product. The three-step yield was 15.4%.

[0639] 1 H-NMR (400MHz, DMSO-d6) δ: 12.08 (s, 1H), 8.11 (s, 1H), 7.78 (d, J = 8.12Hz, 2H), 7.26 (d,J=8.16Hz,2H),7.02(s,1H),6.31-6.10(m,1H),6.05(d,J=19.24Hz,1H),5.63(d, J=12.52Hz,1H),4.72(s,1H),4.40-4.21(m,2H),3.89-3.57(m,8H),2.79-2.61(m,2 H),2.51-2.43(m,4H),1.74-1.71(m,6H),1.51-1.35(m,3H).LC-MS(m / z):501.4(M+H +).

[0640] Example 30 Preparation of 1-(7-(4-(4-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 62)

[0641]

[0642] (1) Preparation of tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0643] 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (512 mg, 1.8 mmol) was dissolved in dioxane (20 ml) and H2O (2 ml), and tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.085 mmol / mL, 18 mL, 1.5 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol) and K2CO3 (622 mg, 4.5 mmol) were added, and the mixture was reacted at 100°C for 2 h under nitrogen atmosphere. The reaction was completed. EA and water were added to the system for extraction and separation, and the organic phase was concentrated. The residue was chromatographed on a silica gel column (DCM / MeOH=50 / 1) to obtain 490 mg of the product with a yield of 67.9%.

[0644] (2) Preparation of tert-butyl 7-(4-(4-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0645] 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (440 mg, 0.91 mmol) was dissolved in dioxane (20 ml) and H2O (4 ml), and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (288 mg, 1.4 mmol), Pd(dppf)Cl2 (66 mg, 0.09 mmol) and K2CO3 (377 mg, 2.7 mmol) were added. The mixture was reacted at 100°C for 3 h under nitrogen atmosphere. The reaction was completed. EA and water were added to the system for extraction and separation. The organic phase was concentrated and the residue was chromatographed on a silica gel column (DCM / MeOH=40 / 1) to obtain 400 mg of the product with a yield of 83.0%.

[0646] (3) Preparation of tert-butyl 7-(4-(4-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0647] 7-(4-(4-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (370 mg, 0.70 mmol) was dissolved in MeOH (15 ml), Pd / C (70 mg) was added, and the reaction was carried out at 25° C. for 6 h under a hydrogen atmosphere. The reaction was completed. The system was filtered under reduced pressure through diatomaceous earth, the filter cake was washed with (DCM / MeOH=10 / 1), the filtrate was combined, and the product was concentrated to 350 mg, with a yield of 94.1%.

[0648] (4) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride

[0649] Tert-butyl 7-(4-(4-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (320 mg, 0.60 mmol) was dissolved in 4M HCl dioxane solution (10 ml) and reacted at 25°C for 2 h. The reaction solution was spin dried and concentrated to obtain the product (250 mg, yield 89.1%).

[0650] (5) Preparation of 1-(7-(4-(4-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0651] The product 30.0 mg was prepared in reference example 25 with a yield of 29.4%.

[0652] 1H-NMR (400MHz, DMSO-d6) δ: 12.44 (s, 1H), 8.65 (s, 1H), 7.86 (d, J = 7.0Hz, 2H), 7.31 (d, J=6.9Hz,2H),7.14(s,1H),6.37-6.20(m,1H),6.11-5.98(m,1H),5.69-5.54(m,1H),4. 08-3.78(m,4H),3.68-3.50(m,4H),3.40-3.20(m,4H),2.82-2.70(m,2H),2.45-2.20(m ,3H),2.03-1.90(m,2H),1.81-1.71(m,2H),1.69-1.60(m,4H).LC-MS(m / z):486.3(M+H + ).

[0653] Example 31 Preparation of 1-(7-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)but-2-yn-1-one (Compound 64)

[0654]

[0655] At 20°C, 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (50 mg, 0.12 mmol) was dissolved in DMF (5 ml), triethylamine (36 mg, 0.36 mmol) was added, but-2-ynoyl chloride (13 mg, 0.13 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 dried on a plate (DCM:MeOH=10:1) to obtain 10 mg of the product. The yield was 17.1%.

[0656] 1 H-NMR (400MHz, DMSO-d6) δ: 12.14 (s, 1H), 8.15 (s, 1H), 7.79 (d, J = 8.12Hz, 2H), 7.79 (d, J = 8.16Hz, 2H), 7.10 (s, 1H), 3.89-3.87 (m, 8H), 3.74-3. 72(m,4H),3.52(s,3H),3.48-3.40(m,2H),3.35-3.20(m,2H),2.79-2.6 1(m,2H),2.51-2.43(m,2H),1.74-1.71(m,4H).LC-MS(m / z):499.3(M+H + ).

[0657] Example 32 Preparation of 1-(7-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one (Compound 67)

[0658]

[0659] To a solution of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (50 mg crude product) in DMF (5 mL) was added DIEA (40 mg, 0.31 mmol) and propionyl chloride (10 mg, 0.11 mmol) at 0°C. The mixture was reacted at 0°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=10:1, Rf~0.3) to obtain 20 mg of the product.

[0660] 1 H-NMR(400MHz,DMSO-d6)δ:12.31(s,1H),8.23(s,1H),7.82(d,J=8.1,2H), 7.29(d,J=8.1,2H),7.11(s,1H),4.40-4.25(m,4H),3.83-3.70(m,2H),3.55 -3.45(m,2H),3.27-3.20(m,6H),2.80-2.70(m,2H),2.40-2.30(m,4H),2.10 -2.00(m,2H),1.80-1.60(m,4H),1.00-0.90(m,3H).LC-MS(m / z):537.1(M+H + ).

[0661] Example 33 Preparation of 1-(7-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 69)

[0662]

[0663] (1) Preparation of tert-butyl 7-(4-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3,5]nonane-2-carboxylate

[0664] 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) was dissolved in dioxane (12 ml) and H2O (2 ml), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (108 mg, 0.42 mmol), Pd(dppf)Cl2 (15 mg, 0.021 mmol) and K2CO3 (87 mg, 0.63 mmol) were added. The mixture was reacted at 100°C for 3 h under nitrogen atmosphere. The reaction was completed. The system was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1) to obtain 100 mg of the product with a yield of 82.4%.

[0665] (2) Preparation of tert-butyl 7-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0666] 7-(4-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester (93 mg, 0.16 mmol) was dissolved in MeOH (30 ml), Pd / C (30 mg) was added, and the reaction was carried out at 25° C. for 8 h under a hydrogen atmosphere. The reaction was completed. The system was filtered under reduced pressure through diatomaceous earth, the filter cake was washed with (DCM / MeOH=10 / 1), the filtrate was combined, and the product was concentrated to 80 mg, with a yield of 86.3%.

[0667] (3) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-2H-thiopyran 1,1-dioxide

[0668] 70 mg of crude product was prepared in step (2) of Reference Example 34.

[0669] (4) Preparation of 1-(7-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0670] The reaction process was carried out in accordance with step (3) of Example 34. The reaction was completed. Water and EA were added to the system for extraction and separation. The organic phase was concentrated to obtain 40 mg of crude product, which was slurried with 5 mL of (DCM / MeOH=20 / 1), filtered under reduced pressure, and the filter cake was dried to obtain 14 mg of product. The two-step yield was 21.9%.

[0671] 1 H-NMR(400MHz,DMSO-d6)δ:12.59(s,1H),8.69(s,1H),7.96-7.88(m,2H),7.40(d,J=7.2Hz ,2H),7.14(s,1H),6.32-6.28(m,1H),6.12-6.08(m,1H),5.69-5.62(m,1H),3.98-3.90(m, 2H),3.80-3.65(m,2H),3.58-3.50(m,2H),3.40-3.20(m,5H),3.10-2.90(m,3H),2.40-2.3 0(m,3H),2.28-2.22(m,2H),2.18-1.99(m,2H),1.98-1.68(m,4H).LC-MS(m / z):534.1(M+H + ).

[0672] Example 34 Preparation of 1-(7-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 75)

[0673]

[0674] (1) Preparation of tert-butyl 7-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.21 mmol) was dissolved in dioxane (12 ml) and H2O (2 ml), (3,5-difluorophenyl)boric acid (66 mg, 0.42 mmol), Pd(dppf)Cl2 (15 mg, 0.021 mmol) and K2CO3 (87 mg, 0.63 mmol), and the mixture was reacted at 100°C for 3 h under nitrogen atmosphere. The reaction was completed. The system was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1) to obtain 80 mg of the product. The yield was 68.1%.

[0675] (2) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0676] Tert-butyl 7-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (70 mg, 0.13 mmol) and TFA (2 mL) were dissolved in DCM (6 mL) and reacted at 25° C. for 2 h. The reaction solution was spin-dried and concentrated to obtain 70 mg of the crude product.

[0677] (3) Preparation of 1-(7-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0678] 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (crude product 70 mg) and triethylamine (49 mg, 0.48 mmol) were dissolved in DMF (8 ml), and a DMF solution (1 mL) containing acryloyl chloride (14 mg, 0.16 mmol) was added dropwise at 0°C, and the reaction was carried out at 25°C for 2 h. The reaction was completed. Water and EA were added to the system for extraction and separation. The organic phase was concentrated and purified on a large silica gel plate (DCM / MeOH=15 / 1) to obtain 34 mg of the product, with a two-step yield of 52.9%.

[0679] 1 H-NMR(400MHz,DMSO-d6)δ:12.80(s,1H),8.84(s,1H),8.01(d,J=8.1Hz,2H ),7.93(d,J=6.7Hz,2H),7.52-7.44(m,2H),7.36(d,J=8.1Hz,2H),6.35-6. 28(m,1H),6.11-6.02(m,1H),5.66-5.62(m,1H),3.88(s,2H),3.59(s,2H), 3.40-3.20(m,2H),2.85-2.76(m,2H),2.50-2.28(m,4H),1.74-1.64(m,4H).

[0680] Example 35 Preparation of 1-(7-(4-(4-(2,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 77)

[0681]

[0682] (1) Preparation of tert-butyl 7-(4-(4-(2,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Referring to Example 34, step (1) gave 80 mg of the product with a yield of 68.1%.

[0683] (2) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(2,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0684] 70 mg of crude product was prepared in step (2) of Reference Example 34.

[0685] (3) Preparation of 1-(7-(4-(4-(2,4-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0686] 30 mg of the product was prepared in step (3) of Reference Example 34, with a two-step yield of 44.9%.

[0687] 1 H-NMR(400MHz,DMSO-d6)δ:12.68(s,1H),8.84(s,1H),7.92-7.88(m,3H),7.52 -7.46(m,1H),7.35-7.28(m,3H),6.96-6.84(m,1H),6.34-6.25(m,1H),6.11-6 .05(m,1H),5.66-5.62(m,1H),3.88(s,2H),3.59(s,2H),3.40-3.20(m,2H),2. 82-2.70(m,2H),2.50-2.28(m,4H),1.74-1.62(m,4H).LC-MS(m / z):514.0(M+H + ).

[0688] Example 36 Preparation of 1-(7-(4-(4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 80)

[0689]

[0690] (1) Preparation of tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0691] Weigh 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 5.4 mmol), tert-butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (crude), Pd(dppf)Cl2 (395 mg, 0.54 mmol), sodium carbonate (1.1 g, 10.4 mmol), dioxane (30 mL) and water (5 mL), replace with nitrogen three times, react at 100 ° C for 12 h, LC-MS showed that the reaction was complete, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, PE: EA = 1: 1-DCM: MeOH = 10: 1) to obtain 1.3 g of the product with a yield of 50.3%.

[0692] (2) Preparation of tert-butyl 7-(4-(4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0693] Weigh tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.41 mmol), (2-fluoro-4-(methylsulfonyl)phenyl)boric acid (89 mg, 0.41 mmol), Pd(dppf)Cl2 (30 mg, 0.041 mmol), sodium carbonate (87 mg, 0.82 mmol), dioxane (10 mL) and water (1 mL), replace with nitrogen three times, react at 100 ° C for 3 h, LC-MS showed that the reaction was completed, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 120 mg of the product, with a yield of 46.7%.

[0694] (3) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0695] To a solution of tert-butyl 7-(4-(4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (120 mg, 0.19 mmol) in MeOH (2 mL) was added HCl / dioxane (4 M, 5 mL) and the mixture was reacted at 20 °C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to give 100 mg of a crude product.

[0696] (4) Preparation of 1-(7-(4-(4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0697] To a solution of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg crude product) in DMF (3 mL) were added DIEA (22 mg, 0.17 mmol) and acryloyl chloride (6 mg, 0.066 mmol), and the mixture was reacted at 0°C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=10:1, Rf~0.4) to give 20 mg of the product.

[0698] 1 H-NMR(400MHz,DMSO-d6)δ:12.80(s,1H),8.89(s,1H),8.20-7.90(m,5H),7.40- 7.30(m,2H),7.02(s,1H),6.35-6.25(m,1H),6.19-6.00(m,1H),5.70-5.60(m,1 H),3.95-3.80(m,2H),3.65-3.60(m,2H),3.50-3.40(m,3H),3.32-3.29(m,4H), 2.80-2.70(m,2H),2.40-2.30(m,2H),1.78-1.60(m,4H).LC-MS(m / z):574.3(M+H + ).

[0699] Example 37 Preparation of 1-(7-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)-2-fluoroprop-2-en-1-one (Compound 82)

[0700]

[0701] 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (50 mg, 0.10 mmol) was dissolved in DMF (5 ml) at 20°C, and DIEA (77 mg, 0.60 mmol), propiolic acid (54 mg, 0.60 mmol) and EDCI (69 mg, 0.36 mmol) were added. The reaction was carried out at 25°C for 12 h. LC-MS showed that the reaction was complete. Water was added, and the product was extracted with EA. The product was spin-dried and dried on a plate (DCM:MeOH=10:1) to obtain 7 mg of the product. The yield was 12.2%.

[0702] 1 H-NMR(400MHz,DMSO-d6)δ:12.30(s,1H),8.24(s,1H),7.82(d,J=8.12Hz,2H), 7.29(d,J=8.16Hz,2H),7.10(s,1H),5.43(d,J=48.5Hz,1H),5.35-5.20(m,1H) ,3.89-3.87(m,8H),3.74-3.72(m,4H),3.51-3.40(m,2H),3.35-3.20(m,2H),2 .79-2.61(m,2H),2.51-2.43(m,2H),1.74-1.71(m,4H).LC-MS(m / z):553.2(M+H + ).

[0703] Example 38 Preparation of 1-(7-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-yn-1-one (Compound 84)

[0704]

[0705] 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.22 mmol) and triethylamine (89 mg, 0.88 mmol) were dissolved in DMF (8 ml), and EDCI (127 mg, 0.66 mmol) and propiolic acid (23 mg, 0.33 mmol) were added. The reaction was carried out at 25°C for 2 h, and the reaction was completed. Water and EA were added to the system for extraction and separation. The organic phase was concentrated and purified on a silica gel plate (DCM / MeOH=15 / 1) to obtain 10 mg of the product, with a yield of 8.9%.

[0706] 1 H-NMR (400MHz, DMSO-d6) δ: 12.91 (s, 1H), 8.84 (s, 1H), 8.01 (d, J = 8.1Hz, 2H), 7.93 (d, J = 6.7Hz, 2H), 7.52-7.44 (m, 2H), 7.36 (d, J = 8.1Hz, 2H) ,4.41(s,1H),3.88(s,2H),3.59(s,2H),3.40-3.20(m,2H),2.85-2.76 (m,2H),2.50-2.28(m,4H),1.74-1.64(m,4H).LC-MS(m / z):512.2(M+H + ).

[0707] Example 39 Preparation of 1-(2-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one (Compound 85)

[0708]

[0709] (1) Preparation of tert-butyl 2-(4-bromophenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0710] To a solution of 2-(4-bromophenyl)acetaldehyde (2.0 g, 10.0 mmol) in MeOH (50 mL) were added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2.3 g, 10.2 mmol), acetic acid (0.5 mL) and sodium cyanoborohydride (1.9 g, 30.3 mmol) at 0°C. The mixture was reacted at 20°C for 2 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated and the residue was diluted with saturated sodium bicarbonate solution. The mixture was extracted with DCM and the organic phase was dried by rotation. The residue was separated by column chromatography (SiO2, PE:EA=3:1-1:2) to give 3.0 g of the product with a yield of 73%.

[0711] (2) Preparation of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0712] Weigh tert-butyl 2-(4-bromophenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3.0 g, 7.3 mmol), bis(boron pinacol) (2.8 g, 11.0 mmol), Pd(dppf)Cl2 (534 mg, 0.73 mmol), potassium acetate (1.4 g, 14.3 mmol) and dioxane (100 mL), replace the atmosphere with nitrogen three times, react at 100 °C for 3 h, LC-MS showed the reaction was complete, the reaction solution was a crude product, and was directly used in the next step.

[0713] (3) Preparation of tert-butyl 2-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0714] Weigh tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (the crude product from the previous step), 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.8 mmol), Pd(dppf)Cl2 (132 mg, 0.18 mmol), sodium carbonate (382 mg, 3.6 mmol), dioxane (15 mL) and water (2 mL), replace with nitrogen three times, react at 100 ° C for 3 h, LC-MS showed that the reaction was completed, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=95:5) to obtain 400 mg of the product.

[0715] (4) Preparation of tert-butyl 2-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0716] Weigh tert-butyl 2-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (400 mg, 0.83 mmol), (3,5-difluorophenyl)boric acid (157 mg, 0.99 mmol), Pd(dppf)Cl2 (61 mg, 0.083 mmol), sodium carbonate (176 mg, 1.7 mmol), dioxane (15 mL) and water (2 mL), replace with nitrogen three times, react at 100 ° C for 3 h, LC-MS showed that the reaction was completed, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 120 mg of the product, with a yield of 26%.

[0717] (5) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-2-yl)ethyl)phenyl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0718] 30 mg of crude product was prepared in step (3) of Reference Example 36.

[0719] (6) Preparation of 1-(2-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one

[0720] Refer to Example 36, step (4) to obtain 20 mg of the product.

[0721] 1 H-NMR(400MHz,DMSO-d6)δ:12.80(s,1H),8.84(s,1H),8.05-7.93(m,2H),7.92-7.80(m,2H),7.55-7.45(m,2H),7.40-7.30(m,2H),6.85-6.70(m ,1H),6.10-6.00(m,1H),5.70-5.60(m,1H),3.60-3.50(m,4H),3.10-2. 90(m,4H),2.70-2.55(m,4H),1.75-1.60(m,4H).LC-MS(m / z):514.3(M+H + ).

[0722] Example 40 Preparation of 7-(4-(4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carbonitrile (Compound 88)

[0723]

[0724] To a solution of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg crude product) in DMF (3 mL) was added 2-bromocyanide (7 mg, 0.066 mmol) and potassium carbonate (24 mg, 0.17 mmol) at 0°C. The mixture was reacted for 1 h at 0°C. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=10:1, Rf~0.3) to give 12 mg of the product.

[0725] 1 H-NMR(400MHz,DMSO-d6)δ:12.79(s,1H),8.89(s,1H),8.20-7.90(m,5H),7.40-7.25(m,2H),7.02(s,1H),3.90-3.70(m,4 H),3.50-3.40(m,5H),2.80-2.70(m,2H),2.50-2.40(m,3H),2.10-1.90(m,1H),1.80-1.60(m,4H).LC-MS(m / z):544.2(M+H) + ).

[0726] Example 41 Preparation of 1-(7-(4-(4-(2-fluoropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 89)

[0727]

[0728] 1-(7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (26 mg), potassium carbonate (30 mg), PddppfCl2 (5 mg) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (15 mg) were dissolved in 5 mL of Dioxane and 0.5 mL of water, and the reaction was carried out at 100° C. under N2 environment for 1 hour. 5 mg of the target product was obtained by concentration column chromatography with a yield of 16.9%.

[0729] 1 H-NMR(400MHz, CDCl3)δ:11.20(m,1H),9.49-9.48(m,2H),8.99-8.95(m,1H),7.76-7.75(m,2H),7.42-7.40(m,2H),7.01(s,1H),6.38 -6.12(m,2H),5.69-5.67(m,1H),3.90-3.76(m,4H),2.91-2.76(m,4H),2.53-2.48(m,4H),1.80-1.75(m,4H).LC-MS(M / e):498.1(M+H) + ).

[0730] Example 42 Preparation of 1-(7-(2-(5-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 91)

[0731]

[0732] (1) Preparation of ethyl 2-(5-bromopyridin-2-yl)methanesulfonate

[0733] Dissolve 2-(5-bromopyridin-2-yl)ethane-1-ol (2.0 g, 10.0 mmol) in DCM (120 ml), add triethylamine (3,5-difluorophenyl) boronic acid (3.0 g, 30.0 mmol), methylsulfonyl chloride (1.7 g, 15.0 mmol), react at 25°C for 30 minutes, and the reaction is complete. Add water to quench, extract with DCM, and spin dry the organic phase to obtain 2.3 g of crude product, which is directly used in the next step.

[0734] (2) Preparation of tert-butyl 7-(2-(5-bromopyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0735] To a solution of ethyl 2-(5-bromopyridin-2-yl)methanesulfonate (2.3 g, crude product) in acetonitrile (60 mL), add tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.3 g, 10.0 mmol) and potassium carbonate (4.1 g, 30.0 mmol). The mixture was reacted at 25°C for 12 hours. After the reaction was completed, the reaction solution was dried and column chromatography (SiO2, DCM:MeOH=50:1) was performed to obtain 1.2 g of the product with a yield of 29.3%.

[0736] (3) Preparation of tert-butyl 7-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0737] To tert-butyl 7-(2-(5-bromopyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.2 g, 2.9 mmol) in dioxane (100 mL), add DPPF palladium dichloride (424 mg, 0.58 mmol), biboronic acid pinacol ester (1.1 g, 4.4 mmol), potassium acetate (853 mmol, 8.7 mmol). The mixture was reacted at 100°C for 12 hours. After the reaction was completed, the reaction solution was directly used for the next step.

[0738] (4) Preparation of tert-butyl 7-(2-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0739] DPPF palladium dichloride (424 mg, 0.58 mmol), 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (809 mg, 2.9 mmol), sodium carbonate (922 mg, 8.7 mmol) and water (20 mL) were added to a solution of tert-butyl 7-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mL, crude product). The mixture was reacted at 100°C for 12 hours. After the reaction was completed, the reaction solution was dried and column chromatography (SiO2, DCM:MeOH=10:1) was performed to obtain 500 mg of the product, with a two-step yield of 35.8%.

[0740] (5) Preparation of tert-butyl 7-(2-(5-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0741] To a solution of tert-butyl 7-(2-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 0.41 mmol) in dioxane (30 mL), DPPF palladium dichloride (60 mg, 0.082 mmol), (3,5-difluorophenyl)boric acid (98 mg, 0.62 mmol), sodium carbonate (130 mg, 1.2 mmol) and water (6 mL) were added. The mixture was reacted at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was dried and column chromatography (SiO2, DCM: MeOH = 10: 1) was performed to obtain 50 mg of the product with a yield of 21.5%.

[0742] (6) Preparation of 6-(6-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)pyridin-3-yl)-4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0743] 70 mg of crude product was prepared in step (2) of Reference Example 34.

[0744] (7) Preparation of 1-(7-(2-(5-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)ethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0745] 24 mg of the product was prepared in step (3) of Reference Example 34, with a two-step yield of 53.0%.

[0746] 1 H-NMR(400MHz,DMSO-d6)δ:12.96(s,1H),9.19(s,1H),8.88(s,1H),8.37(d,J=8.1 Hz,1H),7.93(d,J=6.7Hz,2H),7.64(s,1H),7.52-7.44(m,2H),6.35-6.28(m,1H), 6.11-6.02(m,1H),5.76-5.62(m,1H),3.88(s,2H),3.59(s,2H),3.01-2.85(m,2H) ,2.85-2.76(m,2H),2.50-2.28(m,4H),1.70-1.60(m,4H).LC-MS(m / z):515.3(M+H + ).

[0747] Example 43 3-(6-(4-(2-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-

[0748] Preparation of 5-fluorobenzonitrile (Compound 94)

[0749]

[0750] (1) Preparation of tert-butyl 7-(4-(4-(3-cyano-5-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0751] Weigh tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (150 mg, 0.31 mmol), (3-cyano-5-fluorophenyl)boric acid (66 mg, 0.40 mmol), Pd(dppf)Cl2 (30 mg), sodium carbonate (100 mg, 0.94 mmol), dioxane (10 mL) and water (1 mL), replace with nitrogen three times, react at 100 ° C for 10 h, LC-MS showed that the reaction was completed, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=25:1) to obtain 110 mg of product, yield: 62.4%.

[0752] (2) Preparation of 3-(6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluorobenzonitrile hydrochloride

[0753] HCl / dioxane (4M, 5 mL) was added to tert-butyl 7-(4-(4-(3-cyano-5-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (60 mg, 0.11 mmol), and the mixture was reacted at 20°C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried and the crude product was directly used in the next step.

[0754] (3) Preparation of 3-(6-(4-(2-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluorobenzonitrile

[0755] Referring to Example 36, step (4), 27 mg of the product was prepared with a yield of 49.0%.

[0756] 1 H-NMR(400MHz,DMSO-d6)δ:12.84(s,1H),8.87(s,1H),8.49(s,1H),8.38(d,J=9.4, 1H),8.05-7.90(m,3H),7.46(s,1H),7.35(d,J=8.0,2H),6.34-6.22(m,1H),6.11-6. 03(m,1H),5.66-5.60(m,1H),3.95-3.82(m,2H),3.68-3.52(m,2H),2.84-2.73(m,2 H),2.60-2.57(m,2H),2.43-2.25(m,4H),1.80-1.60(m,4H).LC-MS(m / z): 521.1(M+H + ).

[0757] Example 44 Preparation of 1-(7-(4-(4-(3-fluoro-5-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 95)

[0758]

[0759] (1) Preparation of 2-(3-fluoro-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0760] Weigh 1-bromo-3-fluoro-5-(methylsulfonyl)benzene (50 mg, 0.20 mmol), bis(boron pinacol) ester (76 mg, 0.30 mmol), Pd(dppf)Cl2 (15 mg, 0.021 mmol), potassium acetate (59 mg, 0.60 mmol) and dioxane (10 mL), replace the atmosphere with nitrogen three times, react at 100 °C for 3 h, LC-MS showed the reaction was complete, the reaction solution was a crude product, and was directly used in the next step.

[0761] (2) Preparation of tert-butyl 7-(4-(4-(3-fluoro-5-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0762] Weigh tert-butyl 7-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (96 mg, 0.20 mmol), 2-(3-fluoro-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (crude product), Pd(dppf)Cl2 (15 mg, 0.021 mmol), sodium carbonate (64 mg, 0.60 mmol), dioxane (5 mL) and water (1 mL), replace with nitrogen three times, react at 100°C for 10 h, LC-MS showed that the reaction was complete, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 60 mg of the product, with a yield of 49%.

[0763] (3) Preparation of 6-(4-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)phenyl)-4-(3-fluoro-5-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0764] Refer to Example 36, step (3) to obtain 50 mg of crude product.

[0765] (4) Preparation of 1-(7-(4-(4-(3-fluoro-5-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0766] Refer to Example 36, step (4) to obtain 20 mg of the product.

[0767] 1H-NMR(400MHz,DMSO-d6)δ:12.87(s,1H),8.89(s,1H),8.59(s,1H),8.38(d,J=9.4,1H), 8.05-7.90(m,3H),7.46(s,1H),7.35(d,J=8.0,2H),6.40-6.22(m,1H),6.13-6.03(m,1H) ,5.70-5.60(m,1H),3.95-3.82(m,2H),3.68-3.52(m,2H),3.43-3.39(m,3H),2.84-2.73 (m,2H),2.60-2.57(m,2H),2.43-2.25(m,4H),1.80-1.60(m,4H).LC-MS(m / z):574.1(M+H + ).

[0768] Example 45 Preparation of 1-(2-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one (Compound 104)

[0769]

[0770] (1) Preparation of tert-butyl 2-(4-(4-(1,1-dioxodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0771] Weigh tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (crude product), 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (1.0 g, 2.6 mmol), Pd(dppf)Cl2 (190 mg, 0.26 mmol), sodium carbonate (827 mg, 7.8 mmol), dioxane (40 mL) and water (5 mL), replace with nitrogen three times, react at 100 ° C for 13 h, LC-MS showed that the reaction was complete, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=95:5) to obtain 230 mg of the product with a yield of 15.0%.

[0772] (2) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-2-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide

[0773] Refer to Example 36, step (3) to obtain 220 mg of crude product.

[0774] (3) Preparation of 1-(2-(4-(4-(1,1-dioxodimoroyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one

[0775] 8 mg of the product was prepared in step (4) of Reference Example 36.

[0776] 1 H-NMR(400MHz,DMSO-d6)δ:12.31(s,1H),8.24(s,1H),7.86-7.79(m,2H),7.30- 7.22(m,2H),7.11(s,1H),6.85-6.75(m,1H),6.10-6.00(m,1H),5.70-5.60(m,1 H),4.40-4.27(m,4H),3.60-3.45(m,4H),3.28-3.22(m,4H),3.10-3.00(m,4H), 2.76-2.73(m,2H),2.71-2.66(m,2H),1.70-1.60(m,4H).LC-MS(m / z):535.1(M+H + ).

[0777] Example 46 Preparation of 1-(2-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)-2-fluoroprop-2-en-1-one (Compound 105)

[0778]

[0779] (1) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-2-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide

[0780] To a solution of tert-butyl 2-(4-(4-(1,1-dioxidodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (50 mg, 0.086 mmol) in MeOH (5 mL), HCl / dioxane (4 M, 5 mL) was added and the mixture was reacted at 20° C. for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to give a crude product.

[0781] (2) Preparation of 1-(2-(4-(4-(1,1-dioxodimorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)-2-fluoroprop-2-en-1-one

[0782] To a solution of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-2-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiomorpholine 1,1-dioxide (the crude product from the previous step) in DMF (5 mL), DIEA (0.5 mL), EDCI (50 mg) and 2-fluoroacrylic acid (15 mg) were added and the mixture was reacted at 25 °C for 0.5 h. LC-MS showed that the reaction was complete. The reaction solution was diluted with water and extracted with EA. The organic phase was spin-dried and the residue was separated by prep-TLC (SiO2, DCM:MeOH=10:1, Rf~0.2) to give 12 mg of the product.

[0783] 1 H-NMR(400MHz,DMSO-d6)δ:12.31(s,1H),8.24(s,1H),7.86-7.79(m,2H),7.30-7.22(m,2H),7.11(s,1H),5.30-5.20(m,2H),4.40-4.27(m,4 H),3.60-3.45(m,4H),3.28-3.22(m,4H),3.10-3.00(m,4H),2.76-2.7 3(m,2H),2.71-2.66(m,2H),1.70-1.60(m,4H).LC-MS(m / z):553.1(M+H + ).

[0784] Example 47 Preparation of 1-(8-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]dec-2-yl)prop-2-en-1-one (Compound 111)

[0785]

[0786] (1) Preparation of tert-butyl 8-(4-bromophenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0787] Dissolve p-bromophenylacetaldehyde (2.1 g, 10.6 mmol) in 50 mL of methanol, add tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (3.0 g, 12.5 mmol), acetic acid (1.0 mL) and sodium cyanoborohydride (2.6 g, 41.4 mmol), react the system at 25°C for 2 hours, and quench with water. After concentration, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:1%) to obtain 1.0 g of the product with a yield of 22.4%.

[0788] (2) Preparation of tert-butyl 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0789] Dissolve tert-butyl 8-(4-bromophenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (900 mg, 2.1 mmol) in dioxane (30 mL), add bisborane (1.1 g, 4.3 mmol), potassium acetate (450 mg, 4.6 mmol) and PddppfCl2 (300 mg, 0.41 mmol), and react the system at 100 °C for 3 hours under N2 environment. The reaction solution is directly used for the next step reaction.

[0790] (3) Preparation of tert-butyl 8-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0791] To the reaction solution of the previous step, 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 4.7 mmol), PddppfCl2 (300 mg, 0.41 mmol), 2 mL of water and sodium carbonate (540 mg, 5.1 mmol) were added. The system was reacted at 100 °C for 2 hours under N2 environment and then concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:10%) to obtain 190 mg of the product. The two-step yield was 18.0%.

[0792] (4) Preparation of tert-butyl 8-(4-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0793] 8-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (70 mg, 0.14 mmol) was dissolved in dioxane (10 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (45 mg, 0.17 mmol), 1 mL of water, potassium carbonate (45 mg, 0.33 mmol) and PddppfCl2 (100 mg, 0.14 mmol) were added. The system was reacted at 100°C under N2 environment for 3 hours and then concentrated. The residue was purified by column chromatography (MeOH; DCM=1:1) to obtain 50 mg of the product with a yield of 59.9%.

[0794] (5) Preparation of tert-butyl 8-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0795] 8-(4-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (40 mg) was dissolved in 5 mL of methanol and reacted at 30°C under H2 environment for 5 h. After filtration and concentration, 40 mg of a crude product was obtained.

[0796] (6) Preparation of 4-(6-(4-(2-(2,8-diazaspiro[4.5]dec-8-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)tetrahydro-2H-thiopyran 1,1-dioxide hydrochloride

[0797] 8-(4-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (30 mg, 0.051 mmol) was dissolved in HCl / Dioxane (5 mL), the system was reacted at 30°C for 1 hour and quenched with water. After concentration, the crude product was directly used in the next reaction.

[0798] (7) Preparation of 1-(8-(4-(4-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]dec-2-yl)prop-2-en-1-one

[0799] The crude product from the previous step was dissolved in DMF (5 mL), DIEA (0.1 mL) was added, and acryloyl chloride (9 mg, 0.099 mmol) was added to the system at 0°C. The reaction was terminated after 1 h, and the mixture was washed with concentrated water and extracted with ethyl acetate. The organic phase was concentrated and the residue was subjected to plate chromatography (MeOH:DCM=1:10) to obtain 13 mg of the target product.

[0800] 1 H-NMR(400MHz,DMSO-d6)δ:12.55(s,1H),8.67(s,1H),7.86-7.84(m,2H),7.36-7.34 (m,2H),7.09(s,1H),6.58-6.57(m,1H),6.13-6.09(m,1H),5.63-5.31(m,1H),3.60- 3.58(m,2H),3.56-3.54(m,6H),3.31-3.21(m,4H),2.81-2.71(m,2H),2.45-2.21(m, 5H),2.09-1.95(m,1H),1.87-1.70(m,2H),1.51-1.28(m,5H).LC-MS(M / e):548.1(M+H + ).

[0801] Example 48 Preparation of 1-(7-(2-(6-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)ethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (Compound 114)

[0802]

[0803] (1) Preparation of ethyl 2-(6-chloropyridin-3-yl)methanesulfonate

[0804] 2-(6-chloropyridin-3-yl)ethane-1-ol (2.0 g, 12.7 mmol) and triethylamine (3.9 g, 38.5 mmol) were dissolved in DCM (40 ml), and MsCl (1.7 g, 14.8 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was reacted at 25°C for 3 h. After the reaction was complete, water and DCM were added to extract the liquid, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 2.1 g of crude product.

[0805] (2) Preparation of tert-butyl 7-(2-(6-chloropyridin-3-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0806] 2-(6-chloropyridin-3-yl)methanesulfonic acid ethyl ester (2.1 g crude product), 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.5 g, 15.5 mmol), potassium carbonate (5.3 g, 38.4 mmol) were dissolved in acetonitrile (80 ml) and reacted at 85°C for 12 h. The reaction was completed. Water and EA were added to the system for extraction and separation. The organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: MeOH = 50:1) to obtain 3.0 g of the product. The two-step yield was 64.7%. (3) Preparation of tert-butyl 7-(2-(6-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)ethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0807] Refer to Example 34, step (1) to obtain 166 mg of product, with a yield of 25.0%.

[0808] (4) Preparation of 4-(6-(5-(2-(2,7-diazaspiro[3.5]non-7-yl)ethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0809] 160 mg of crude product was prepared in step (2) of Reference Example 34.

[0810] (5) Preparation of 1-(7-(2-(6-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)ethyl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one

[0811] 64 mg of the product was prepared in step (3) of Reference Example 34, with a two-step yield of 57.1%.

[0812] 1 H-NMR(400MHz,DMSO-d6)δ:12.26(s,1H),8.46(s,1H),8.19(s,1H),7.92(d,J=8.2Hz ,1H),7.71(d,J=8.2Hz,1H),7.33(s,1H),6.34-6.25(m,1H),6.11-6.05(m,1H),5.66- 5.62(m,1H),3.90-3.85(m,6H),3.81-3.75(m,4H),3.62-3.58(m,2H),3.40-3.30(m, 2H),2.80-2.70(m,2H),2.50-2.28(m,4H),1.74-1.62(m,4H).LC-MS(m / z):488.0(M+H + ).

[0813] Example 49 Preparation of 1-(2-(4-(4-morpholin-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one (Compound 115)

[0814]

[0815] (1) Preparation of tert-butyl 2-(4-(4-morpholine-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0816] Referring to Example 34, step (1), 99 mg of the product was prepared with a yield of 15.0%.

[0817] (2) Preparation of 4-(6-(4-(2-(2,7-diazaspiro[3.5]non-2-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine

[0818] 90 mg of crude product was prepared in step (2) of Reference Example 34.

[0819] (3) Preparation of 1-(2-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one

[0820] 15 mg of the product was prepared in step (3) of Reference Example 34, with a two-step yield of 21.9%.

[0821] 1H-NMR(400MHz,DMSO-d6)δ:12.15(s,1H),8.17(s,1H),7.92-7.81(m,2H),7.32 -7.15(m,2H),7.11(s,1H),6.82-6.68(m,1H),6.11-5.95(m,1H),5.66-5.62(m,1 H),3.92-3.80(m,4H),3.80-3.75(m,4H),3.40-3.30(m,2H),3.10-2.90(m,5H), 2.60-2.50(m,4H),2.05-1.90(m,1H),1.70-1.58(m,4H).LC-MS(m / z):489.0(M+H + ).

[0822] Example 50 Preparation of 1-(8-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]dec-2-yl)prop-2-yn-1-one (Compound 122)

[0823]

[0824] 8-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane hydrochloride (90 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), HATU (137 mg, 0.36 mmol) and triethylamine (91 mg, 0.90 mmol) were added, stirred for 10 minutes, propiolic acid (25 mg, 0.36 mmol) was added, and the mixture was reacted at 10°C for 16 hours. Water was added to quench the mixture, and the mixture was extracted with water and ethyl acetate. The organic phase was washed with water and purified by prep-TLC (dichloromethane: methanol = 10: 1) to obtain 7 mg of the product with a yield of 7.5%. LC-MS (m / z): 526.2 (M+H + ).

[0825] 1 H-NMR(400MHz,DMSO-d6)δ:12.80(s,1H),8.83(s,1H),8.05-7.99(m,2H),7.92-7.91(m,2H),7.49-7.43(m,2H),7.36-7.34(m,2H),4.44(s ,1H),3.65-3.50(m,1H),3.45-3.20(m,5H),2.85-2.75(m,2H),2.65- 2.55(m,2H),2.50-2.35(m,2H),1.80-1.60(m,2H),1.55-1.40(m,4H).

[0826] Example 51 Preparation of 8-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane-2-carbonitrile (Compound 123)

[0827]

[0828] 8-(4-(4-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenethyl)-2,8-diazaspiro[4.5]decane hydrochloride (90 mg, 0.18 mmol) and triethylamine (91 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (5 mL), cyanogen bromide (38 mg, 0.36 mmol) was added, and the mixture was reacted at 10°C for 3 hours. Water was added to quench the mixture, and the mixture was extracted with water and ethyl acetate. The organic phase was washed with water and purified by prep-TLC (dichloromethane: methanol = 10: 1) to obtain 12 mg of the product with a yield of 13.6%.

[0829] 1 H-NMR(400MHz,DMSO-d6)δ:12.78(s,1H),8.83(s,1H),8.10-7.98(m,2H),7.92-7.90(m,2H),7.48-7.42(m,2H),7.38-7.33(m,2H),3.55-3.40(m ,4H),3.15-3.10(m,2H),2.84-2.78(m,2H),2.70-2.55(m,2H),2.50-2. 35(m,2H),1.80-1.70(m,2H),1.55-1.40(m,4H).LC-MS(m / z):499.2(M+H + ).

[0830] The compounds shown in the following table were prepared using the same or similar methods as in the above examples:

[0831] serial number <![CDATA[LC-MS(M / e,M+H + )]]> serial number <![CDATA[LC-MS(M / e,M+H + )]]> serial number <![CDATA[LC-MS(M / e,M+H + )]]> Compound 3 501.3 Compound 6 529.3 Compound 8 543.3 Compound 10 517.3 Compound 12 543.3 Compound 14 557.3 Compound 15 571.3 Compound 20 487.2 Compound 24 471.2 Compound 25 448.2 Compound 27 475.2 Compound 28 446.2 Compound 29 473.2 Compound 30 505.2 Compound 31 461.2 Compound 34 501.2 Compound 37 501.2 Compound 39 508.2 Compound 40 535.2 Compound 41 513.2 Compound 42 515.2 Compound 43 513.3 Compound 44 447.2 Compound 45 525.2 Compound 49 472.3 Compound 50 487.3 Compound 51 523.2 Compound 54 491.3 Compound 55 476.3 Compound 59 488.3 Compound 60 502.3 Compound 61 503.3 Compound 63 537.3 Compound 65 505.3 Compound 66 486.3 Compound 68 523.2 Compound 70 534.2 Compound 71 520.3 Compound 72 549.2 Compound 73 501.2 Compound 74 489.3 Compound 77 514.2 Compound 78 548.2 Compound 79 555.3 Compound 81 592.2 Compound 83 532.2 Compound 85 514.2 Compound 86 513.2 Compound 87 572.2 Compound 90 515.2 Compound 92 542.3 Compound 93 528.2 Compound 96 567.2 Compound 97 552.2 Compound 98 550.2 Compound 99 552.2 Compound 100 552.2 Compound 101 553.2 Compound 102 564.2 Compound 103 568.2 Compound 106 533.2 Compound 107 506.2 Compound 108 534.2 Compound 109 578.2 Compound 110 549.3 Compound 112 501.3 Compound 113 486.3 Compound 116 501.2 Compound 117 528.2 Compound 118 532.3 Compound 119 519.3 Compound 120 504.3 Compound 121 528.2 Compound 124 486.3 Compound 125 515.2 Compound 126 499.2

[0832] 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, and the description of the above examples is only used to help understand the method of the present invention. It should be pointed out that for those of ordinary skill in the art, the present invention can also be improved and modified 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 (IX), a pharmaceutically acceptable salt, ester or stereoisomer thereof, in, Z1, Z2, Z3, and Z4 are independently selected from CR a or N; X1, X2, and X4 are 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, CR a1 R b1 or NR c1 ; Y3, Y4, Y5, and Y6 are independently selected from CR a R b 、C(O)、S(O)2、O、S or NR c ; 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 )-、-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; Each R1, R2, each R3, each R a , each R b , each R a2 , each R b2 , each R a3 , each R b3 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, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; Each R c , each R c1 , each R c2 , each R c3 , each 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)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-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, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by 1-3 substituents, each of which 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; m and q are each independently an integer from 0 to 4; n is an integer from 1 to 4; n3 and n4 are each independently an integer of 1 to 4; n1' and n2' are each independently selected from integers of 1-3.

2. The compound according to claim 1, its pharmaceutically acceptable salt, ester or stereoisomer thereof, in, X1, X2, and X4 are 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, 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 )-、-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; Each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3 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, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-8 membered heteroaryl; R c , R c1 , each R c2 , each R c3 , each 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)-C(R a3 )=C(R a3 )(R b3 )、-C(O)-R a3 、-C(O)-C(R a2 )(R b2 )-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, the C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by 1-3 substituents, each of which is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; m and q are each independently an integer from 0 to 4; n is an integer from 1 to 4; n1 and n2 are each independently an integer from 0 to 3; n3 and n4 are each independently an integer of 1-4.

3. The compound according to claim 1 or 2, or a 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 is selected from N or CR a ; Y1 is 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 -C(O)-, -N(R c2 )-、-C(R a2 )(R b2 )-, -S(O)2-; 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; Each R1, R2, each R3, each R a , R b , each R a2 , each R b2 , each R a3 , each R b3 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 Alkylsulfonyl, C 1-6 Alkylaminosulfonyl, C 1-6 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; R c , R c1 , each R c2 , each R c3 , each 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 a2 )(R b2 )-R a3 、-C(O)-C(R a3 )=C(R a3 )(R b3 ), -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; m and q are each independently an integer from 0 to 3; n is an integer from 1 to 3; n1 and n2 are each independently an integer from 0 to 2; n3 and n4 are each independently an integer of 1-3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein: Select from the following structures: Y1 is selected from CH or N; Y2 is selected from O, CR a1 R b1 or NR c1 ; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; -(L)n- is selected from -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 ); 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 b2 , each R a3 , each R b3 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-4 Alkylsulfonyl, C 1-4 Alkylaminosulfonyl, C 1-4 Alkylsulfonylamino, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group; R c , R c1 , each R c2 , each R c3 , each 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)-CH2-R a3 、-C(O)-CH(CH3)-R a3 , -C(O)-CH=CH2, -C(O)-C(F)=CH2, -C(O)-C(Cl)=CH2, -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, the C 1-4 Alkyl, C 1-4 Alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl are optionally substituted by 1-3 substituents, and the substituents are independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; m and q are independently 0, 1, and 2; n1 and n2 are independently 0, 1, and 2; n3 and n4 are independently 1 and 2, respectively.

5. The compound according to claim 4, 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-dioxane, 1,3-dioxane, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophene 1,1-dioxide, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 3-morpholinone, morpholine-3,5-dione; -(L)n- is selected from -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)-; 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; Each R1, R2, each R3, R a , each R a3 , 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, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R c , R c1 , each R c3 , each 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)-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)-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, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl.

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, 1,4-dioxane, 1,3-dioxane, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 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)-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, -C(O)-O-CH2CH3; Each R c1 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)-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)-NH2, -S(O)2-CH=CH2, -S(O)2-CH3, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, 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.

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