Nitrogen-containing heteroaryl compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a nitrogen-containing heteroaromatic ring compound, and a preparation method therefor and the use thereof. The nitrogen-containing heteroaromatic ring compound has a structure as shown in formula I, wherein the definitions of M, X, A, E, G, Z, L1, L2, Y1, Y2, R1 and R2 are as described in the description. The nitrogen-containing heteroaromatic ring compound has an effective and highly selective inhibitory effect on epidermal growth factor receptor 2 (HER2), and thus can be used in the treatment of related diseases induced by HER2 abnormalities, especially in the treatment of cancer diseases.

Description

Nitrogen-containing heteroaryl compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a nitrogen-containing heteroaryl compound and a preparation method and application thereof. Background Art

[0002] The epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21). It is one of the four members of the ErbB family (EGFR / HER1 / ErbB1, HER2 / ErbB2, HER3 / ErbB31, and HER4 / ErbB4) and possesses tyrosine kinase activity. Currently, no ligand has been found that can directly interact with HER2. HER2 can form heterodimers with other members of the ErbB family, activating the downstream MEK / ERK / MAPK pathway and the PI3K / AKT bypass pathway for signal transduction, ultimately promoting cell growth, proliferation, and division.

[0003] Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been linked to numerous cancers, including breast, colorectal, gastric, non-small cell lung, head and neck, ovarian, cervical, bladder, esophageal, endometrial, and glioblastoma. The prevalence of HER2 overexpression in lung, breast, gastric, bile duct, ovarian, and endometrial cancers is approximately 2.5%, 15% to 25%, 20%, 20%, 27%, and 18% to 80%, respectively.

[0004] The detection rate of HER2 mutations in non-small cell lung cancer is approximately 2%-4%, of which exon 20 insertion mutations account for 71% of HER2 mutations, including common subtypes such as A772_G775dup (55.0%), G776delinsVC (8.3%), G778_P780dup (5.6%), and G776delinsLC (2.1%). Other HER2 mutations include exon 19 mutation L755P (1.9%), exon 21 mutation V842I (0.7%), transmembrane domain mutations V659E (4.1%) and G660D (0.9%), and extracellular region mutations D277Y (1.9%), S310F (7.7%), S310Y (1.9%), and A466V (1.4%). In addition, studies have shown that patients with HER2-abnormal cancers are more likely to develop central nervous system metastases during the course of the disease. Approximately 47% of patients with HER2-mutated non-small cell lung cancer develop brain metastases, which are associated with poor prognosis.

[0005] Currently, clinically approved drugs for the treatment of HER2 abnormalities include monoclonal antibodies (mAbs) (trastuzumab, pertuzumab, etc.), small molecule tyrosine kinase inhibitors (TKIs) (lapatinib, tucatinib, neratinib, pyrotinib, etc.) and antibody-drug conjugates (ADCs) (enmetazocine, trastuzumab dextromethorphan).

[0006] Monoclonal antibodies and antibody-drug conjugates have poor selectivity for wild-type EGFR. As large molecules, they are not easily able to cross the blood-brain barrier. Furthermore, some patients develop resistance or relapse after a period of monoclonal antibody (mAb) use. Currently approved TKIs include selective TKIs (tucatinib) and non-selective TKIs (lapatinib, narecoxib, and pyrotinib). These TKIs exhibit moderate anti-tumor activity against wild-type HER2 but are less effective against the most common HER2 exon 20 insertion mutation. Furthermore, non-selective TKIs have poor selectivity for wild-type EGFR and are prone to adverse reactions such as rash and diarrhea. Therefore, the development of HER2 inhibitors that are selective, can cross the blood-brain barrier, and have potential inhibitory effects against HER2 exon 20 insertion mutations is of great significance.

[0007] Summary of the Invention

[0008] In order to address the defects of the prior art, the present invention aims to provide a nitrogen-containing heteroaryl compound and its preparation method and application, which has good activity in inhibiting HER2 exon 20 insertion mutation and has high selectivity for wild-type EGFR.

[0009] The present invention is achieved through the following technical solutions.

[0010] In a first aspect, the present invention provides a compound having a structure as shown in Formula I below, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof:

[0011] Wherein, in Formula I,

[0012] M is N or CR 3 ;

[0013] X is N or CR 4 ;

[0014] A is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylthio, 3-12 membered cycloalkylthio, 3-12 membered heterocyclylthio, 3-12 membered cycloalkyl-C 1-6 Alkylene-mercapto or 3-12 membered heterocyclyl-C 1-6 Alkylene-mercapto, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylthio, 3-12 membered cycloalkylthio, 3-12 membered heterocyclylthio, 3-12 membered cycloalkyl-C 1-6 Alkylene-mercapto and 3-12 membered heterocyclyl-C 1-6 Alkylene-mercapto is optionally substituted with one or more R';

[0015] Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted by one or more R′;

[0016] Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more R′;

[0017] Z is C(=O) or S(O)2;

[0018] L1 is NR 8 ,O,CR 5 R 6 , S, S(O) or S(O)2;

[0019] L2 is a chemical bond, O, NR 8 , CR 5 R 6 , C(═O), S, S(O) or S(O) 2 ;

[0020] E is a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are optionally substituted by one or more R e replace;

[0021] G is described optionally substituted with one or more R′;

[0022] -- is none or a single key;

[0023] Ring B is a 5-6 membered heteroaryl, a 5-7 membered heterocyclyl or a 5-7 membered cycloalkyl;

[0024] X 1 is a chemical bond, N, CH, CH2, O, S, S(O) or S(O)2;

[0025] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0026] X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0027] X 5 is a chemical bond, N, CH, CH2, O, S, S(O) or S(O)2;

[0028] X 6 is N, O, S, C(=O), S(O), S(O)2, N(=O), N(O)2, N + -O - or CH;

[0029] R 1 For halomethyl, C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl, the C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide and C 4-6 Cycloalkenyl is optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, 6-12 membered aryl, C 1-3 Alkoxy-C 1-3 Alkyl- or NR a Rb Substitute, the C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl and C 1-3 Alkoxy-C 1-3 Alkyl - optionally substituted with one or more R';

[0030] R 2 For hydrogen atoms, deuterium atoms, halogens, cyano groups, hydroxyl groups, amino groups, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl or 3-12 membered heterocyclic group, the hydroxyl, amino, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more R's;

[0031] R 3 For hydrogen atoms, deuterium atoms, halogens, cyano groups, hydroxyl groups, amino groups, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c Rd NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted with one or more R';

[0032] R 4 For hydrogen atoms, halogen, cyano, amino, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, said amino, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted with one or more R';

[0033] R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclyl-C 1-6 Alkyl-, the hydroxyl, amino, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- and 3-12 membered heterocyclyl-C 1-6 Alkyl - optionally substituted with one or more R';

[0034] or R 5 With R 6 Together with the C atom to which it is attached, it forms a 3-12 membered cycloalkyl or a 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and the 3-12 membered heterocyclyl are optionally substituted by one or more R′;

[0035] R 7 For hydrogen atoms, C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 haloalkyl, 5-12 membered heteroaryl or 6-12 membered aryl, the C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Haloalkyl, 5-12 membered heteroaryl and 6-12 membered aryl are optionally substituted with one or more R';

[0036] R 8 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 Alkyl- or hydroxyl C 1-6 alkyl;

[0037] R a and R b are independently a hydrogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic-C 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4Alkyl- or deuterated C 1-4 Alkyl, the C 1-4 Alkyl, C 1-4 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic-C 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- and deuterated C 1-4 Alkyl is optionally substituted with one or more R';

[0038] or R a With R b Together with the N atom to which it is attached, it forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally substituted with one or more R's;

[0039] R c and R d are independently a hydrogen atom, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclyl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 Alkyl- and 3-12 membered heterocyclyl-C 1-6 Alkyl - optionally substituted with one or more R';

[0040] R e For deuterium atoms, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, OR e1 SR e1 、SOR e1 、SO2R e1 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 NR e1 R e2 NR e1C(=O)R e2 、OC(=O)R e1 ,SONR e1 、SO2NR e1 、NHS(O)2R e1 、NHS(O)R e1 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、-(O)(OR e1 )2 or P(O)(R e1 )2, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Heteroalkenyl, C 2-6 Heteroalkynyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, C 1-6 Haloalkyl and C 1-6 Haloalkoxy is optionally substituted with one or more R';

[0041] R e1 and R e2 are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group or R e1 and R e2 Together with the attached nitrogen atom, it forms a 3-12 membered heterocyclic group;

[0042] R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy or oxo (=O).

[0043] In certain embodiments, in Formula I, M is N or CR 3 ;

[0044] R 3 For hydrogen atoms, deuterium atoms, F, Cl, Br, cyano, hydroxyl, amino, C 1-6Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted with one or more R';

[0045] R c and R d Each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group, optionally substituted by one or more R's;

[0046] R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or oxo (═O);

[0047] Preferably, in formula I, M is N or CR 3 ;

[0048] R3 For hydrogen atoms, deuterium atoms, F, Cl, Br, cyano, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or NR c C(=O)R d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and NR c C(=O)R d Optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo.

[0049] More preferably, in formula I, M is N or CR 3 ;

[0050] R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-propoxy group, a piperazin-1-yl-propoxy group, a pyrrolidin-1-yl-ethoxy group, a pyrrolidin-1-yl-propoxy group, a tetrahydrofuran-3-oxy group, a methylthio group, a methylamino group, an ethylamino group, an acetamido group, a propionamido group, a methoxyethyl group, a methoxyethylamino group or a methoxyethoxy group.

[0051] In certain embodiments, in Formula I, X is N or CR 4 ;

[0052] R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

[0053] R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

[0054] Preferably, in formula I, X is N or CR 4 ;

[0055] R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

[0056] R' is a deuterium atom, F, Cl, a cyano group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a methoxy group.

[0057] In certain embodiments, in Formula I, A is C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy or 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, the C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy and 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy is optionally substituted with one or more R′;

[0058] Preferably, A is ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy or tetrahydropyrrolylmethyleneoxy, and the ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5] Nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy and tetrahydropyrrolylmethyleneoxy are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy.

[0059] More preferably, A is selected from the following groups:

[0060] Optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy.

[0061] In certain embodiments, in Formula I, Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0062] R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino or 3-12 membered cycloalkyl-C 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino and 3-12 membered cycloalkyl-C 1-6 Alkyl - optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0063] or R 5 and R 6 Together with the C atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0064] Preferably, in Formula I, Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl being optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0065] R 5 and R 6 each independently represents a hydrogen atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0066] or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl group, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl groups are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups.

[0067] In certain embodiments, in Formula I, Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0068] R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;

[0069] Preferably, in Formula I, Y 2 is a chemical bond, acridinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl or NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl.

[0070] In certain embodiments, in Formula I, Z is C(═O) or S(O) 2 .

[0071] In certain embodiments, in Formula I, L1 is NR 8 or O;

[0072] R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxyl group. 1-6 ethyl;

[0073] Preferably, in Formula I, L1 is NR 8 ;

[0074] R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group.

[0075] In certain embodiments, in Formula I, L2 is a bond, O, CH, or C(=O).

[0076] In certain embodiments, in Formula I, E is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by one or more R e replace;

[0077] R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

[0078] Preferably, in formula I, E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally replaced by one or more R e replace;

[0079] R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2, the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted by one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl.

[0080] In certain embodiments, in Formula I, G is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0081] -- is none or a single key;

[0082] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0083] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0084] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0085] X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0086] X 5 is a chemical bond, N, CH, CH2, O or S;

[0087] X 6 is N, O, S or CH;

[0088] Preferably, in formula I, G is selected from the following groups:

[0089] Optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

[0090] More preferably, in formula I, G is selected from the following groups:

[0091] In certain embodiments, in Formula I, R 1is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl group are optionally substituted by one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, epoxypropanyl, epoxybutanyl, deuterium atom, phenyl, pyridyl or NR a R b Substituted, the methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl and pyridinyl are optionally substituted with one or more R';

[0092] R a and R b are each independently a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an acridinylmethyl group or an acridinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the adamantyl group, the methoxyethyl group, the cyclopropylmethyl group, the cyclobutylmethyl group, the cyclopropylethyl group, the cyclobutylethyl group, the acridinylmethyl group and the acridinylethyl group are optionally substituted with one or more R′;

[0093] or R a With R b and the N atom to which it is attached form an acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl group, said acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl group being optionally substituted with one or more R′;

[0094] R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, or oxo (═O);

[0095] Preferably, in Formula I, R 1 Selected from the following groups:

[0096] In certain embodiments, in Formula I, R 2 For hydrogen atoms, deuterium atoms, F, Cl, cyano groups, amino groups, C 1-4 Alkyl or 3-6 membered cycloalkyl;

[0097] Preferably, in Formula I, R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0098] In certain embodiments, in Formula I:

[0099] M is N or CR 3 ;

[0100] R 3 For hydrogen atoms, deuterium atoms, F, Cl, Br, cyano, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted with one or more R';

[0101] R c and R d Each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group, optionally substituted by one or more R's;

[0102] X is N or CR 4 ;

[0103] R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

[0104] A is C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy or 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, the C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy and 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy is optionally substituted with one or more R′;

[0105] Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0106] R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino or 3-12 membered cycloalkyl-C 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino and 3-12 membered cycloalkyl-C 1-6 Alkyl - optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0107] Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0108] R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;

[0109] Z is C(=O) or S(O)2;

[0110] L1 is NR 8 or O;

[0111] R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxyl group. 1-6 ethyl;

[0112] L2 is a chemical bond, O, CH or C(=O);

[0113] E is phenyl or 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl are optionally substituted by one or more R e replace;

[0114] R eis a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

[0115] G is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0116] -- is none or a single key;

[0117] Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0118] X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0119] X 2 is N, CH, CH2, O, S, S(O) or S(O)2;

[0120] X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 、X 2 and X 3 Not all N at the same time;

[0121] X 5 is a chemical bond, N, CH, CH2, O or S;

[0122] X 6 is N, O, S or CH; or

[0123] R1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl group are optionally substituted by one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, epoxypropanyl, epoxybutanyl, deuterium atom, phenyl, pyridyl or NR a R b Substituted, the methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl and pyridinyl are optionally substituted with one or more R';

[0124] R a and R b are each independently a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an acridinylmethyl group or an acridinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the adamantyl group, the methoxyethyl group, the cyclopropylmethyl group, the cyclobutylmethyl group, the cyclopropylethyl group, the cyclobutylethyl group, the acridinylmethyl group and the acridinylethyl group are optionally substituted with one or more R′;

[0125] or R a With R b and the N atom to which it is attached form an acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl group, said acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, or 2-azabicyclo[3.1.0]hexanyl group being optionally substituted with one or more R′;

[0126] R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, or oxo (═O);

[0127] R 2 For hydrogen atoms, deuterium atoms, F, Cl, cyano groups, amino groups, C 1-4 Alkyl or 3-6 membered cycloalkyl.

[0128] In other specific embodiments, in Formula I:

[0129] M is N or CR 3 ;

[0130] R 3 For hydrogen atoms, deuterium atoms, F, Cl, Br, cyano, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or NR c C(=O)R d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and NR c C(=O)R d Optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo;

[0131] X is N or CR 4 ;

[0132] R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

[0133] R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

[0134] A is ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy or tetrahydropyrrolylmethyleneoxy, and the ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane , phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy, and tetrahydropyrrolylmethyleneoxy are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, or methoxy;

[0135] Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl being optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0136] R 5 and R 6 each independently represents a hydrogen atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0137] or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl groups are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0138] Y 2 is a chemical bond, acridinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl or NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl groups are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino groups;

[0139] R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;

[0140] Z is C(=O) or S(O)2;

[0141] L1 is NR 8 ;

[0142] R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group;

[0143] L2 is a chemical bond, O, CH or C(=O);

[0144] E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally replaced by one or more R e replace;

[0145] R eis a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2, the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

[0146] G is selected from the following groups:

[0147] optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0148] R 1 Selected from the following groups:

[0149] R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0150] In some further embodiments, in Formula I:

[0151] M is N or CR 3 ;

[0152] R 3is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-propoxy group, a piperazin-1-yl-propoxy group, a pyrrolidin-1-yl-ethoxy group, a pyrrolidin-1-yl-propoxy group, a tetrahydrofuran-3-oxy group, a methylthio group, a methylamino group, an ethylamino group, an acetamido group, a propionamido group, a methoxyethyl group, a methoxyethylamino group, or a methoxyethoxy group;

[0153] X is N or CR 4 ;

[0154] R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R's;

[0155] R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

[0156] A is selected from the following groups:

[0157] optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, or methoxy;

[0158] Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl being optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

[0159] R 5 and R 6each independently represents a hydrogen atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0160] or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl groups are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

[0161] Y 2 is a chemical bond, acridinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl or NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl groups are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino groups;

[0162] R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl;

[0163] Z is C(=O);

[0164] L1 is NR 8 ;

[0165] R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group;

[0166] L2 is a chemical bond, O, CH or C(=O);

[0167] E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally replaced by one or more R e replace;

[0168] R eis a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

[0169] G is selected from the following groups:

[0170] R 1 Selected from the following groups:

[0171] R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0172] In a more specific embodiment, the compound represented by formula I is selected from the following compounds:

[0173] In a second aspect, in certain embodiments, the present invention provides a method for preparing a compound of formula I, comprising the following reaction steps:

[0174] (1) Compound I-1 and Compound I-2 undergo coupling or substitution reaction to form Compound I-3;

[0175] (2) Compound I-3 and Compound I-4 undergo coupling or substitution reaction to form Compound I-5;

[0176] (3) deprotection of compound I-5 to form compound I-6;

[0177] (4) Compound I-6 and Compound I-7 undergo a condensation reaction to form a compound represented by Formula I;

[0178] In certain embodiments, the present invention provides another method for preparing a compound of formula I, comprising the following reaction steps:

[0179] Compound I-3 and compound I-8 undergo coupling or substitution reaction to form a compound represented by formula I;

[0180] In certain embodiments, the present invention provides another method for preparing compound I-3, comprising the following reaction steps:

[0181] Compound I-9 and compound I-10 undergo coupling or substitution reaction to form compound I-3;

[0182] Among them M, X, A, E, G, Z, L1, L2, Y 1 、Y 2 、R 1 and R 2 The definition of is as above; H is a hydrogen atom; X a is a chlorine atom; X b is a bromine atom, an iodine atom or a hydroxyl group; X c is hydrogen, halogen, OMs, -B(OH)2 or X d is a bromine atom or an iodine atom; G a For Boc, G b Cl, OH or -OZR 1 .

[0183] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient;

[0184] Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays.

[0185] In a fourth aspect, the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient in the treatment of diseases mediated by abnormal HER2;

[0186] Preferably, the disease is a tumor disease;

[0187] More preferably, the tumor disease includes: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0188] In a fifth aspect, the present invention provides a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

[0189] The patient is preferably a mammal, and the mammal is preferably a human.

[0190] In certain embodiments, the administration routes include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, and nasal administration.

[0191] In some embodiments, the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma, or mesothelioma.

[0192] The compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions can be introduced into the body through any suitable route, such as oral administration, intravenous injection, intranasal administration, external application, intramuscular injection, intradermal injection, transdermal administration or subcutaneous administration.

[0193] In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof, can be formulated into dosage forms suitable for drug release and administered by injection (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intrathecal, intracardial, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes of administration (e.g., oral, enteral, buccal, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).

[0194] Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral administration such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and the preparation methods and processes are well known, for example, as provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0195] In certain embodiments, HER2 abnormality refers to HER2 gene mutation, HER2 amplification, or HER2 overexpression;

[0196] Preferably, the HER2 gene mutation includes mutations in exons 18-21, transmembrane domain mutations, and extracellular region mutations; the mutations include point mutations, deletion mutations, and insertion mutations;

[0197] More preferably, the exon 20 insertion mutations include Y772_A775dup, G776delinsVC, G778_P780dup, G776delinsLC, E770delinsEAYVM, E770_A771insAYVM, M774delinsWLV, A775delinsAYVMA, A775_G776insVVMA, A775_G776insSVMA, A775_G776insTVMA, G776delinsAVGC, G776delinsVV, G776delinsVG, G776_V777delGinsCVC, G776_V777delGinsVC, V777delinsAPL, V777_G778insC, G778insGSP, G778_S779insCPG; exon 20 point mutations include G776C, G776D, G776S, G776V, V777L, D778H, V782I, T791A, L806P, R811L, N813T, R816C, Q820K, Q828H.

[0198] In certain embodiments, the compounds or pharmaceutical compositions of the present invention can be administered simultaneously with one or more other pharmacologically active substances, thereby achieving additive or even synergistic effects in vivo. For example, the compounds of the present invention can be combined with other pharmacologically active substances to form a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Additional pharmacologically active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal / diabodies, or ADCs, such as osimertinib, ametinib, vumetinib, befortinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emtansinetrastuzumab, denatinib, and the like; 2) monoclonal / diabodies or ADCs that are inhibitors of downstream pathways or other pathway targets, such as, but not limited to, MEK, RET, PI3K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (such as CDK4 / 6).Such as: Trametinib, Bimetinib, Selumetinib, Palacitinib, Idranib, Copanlisib, Duvelisib, Alpelisib, Umbralisib, Parsaclisib, Rapamycin, Temsirolimus, Everolimus, Capmatinib, Tepotinib, Saivotinib, Gumetinib, Berretinib, Cabozantinib, Emibetuzumab, Telisotuzumab, Niraparib, Palbociclib, Ribociclib, Abemaciclib, etc. ; 3) Anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) Apoptosis inducers (such as Bcl-2), such as obatoclax, venetoclax, etc.; 5) Chemotherapeutic drugs, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carboplatin, Mustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, daunorubicin, dienestilbestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole Azoles, leucovorin, pentostatin, mithramycin, procarbazine, raltitrexed, porfibril sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, lomustine, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triazolam, methyl chloride, topotecan titanocene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0199] In certain embodiments, the compounds provided herein can be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents that reverse multidrug resistance in tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

[0200] In certain embodiments, the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be used concurrently with radiotherapy. In certain embodiments, the compounds provided herein can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of these therapies.

[0201] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0202] It is particularly important to note that similar substitutions and modifications made to the present invention will be obvious to those skilled in the art and are considered to be included in the present invention. It is obvious that relevant persons can modify or appropriately change and combine the methods and applications described herein to implement and apply the technology of the present invention without departing from the content, spirit, and scope of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0203] Unless otherwise specified, the present invention was carried out under conventional conditions or those recommended by the manufacturer. The raw materials or excipients, as well as the reagents or instruments used, for which the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0204] Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention.

[0205] Indicates the junction site.

[0206] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix (C a-b )alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C 1-6 ) Alkyl refers to an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or linear.

[0207] The atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.

[0208] "Alkyl" refers to a linear or branched, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and other similar groups. 1-8 Alkyl. More preferably C 1-6Alkyl. More preferably C 1-4 alkyl.

[0209] The alkyl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: deuterium atoms, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O), -C 0-6 Alkyl-OR e1 、-C 0-6 Alkyl-SR e1 、-C 0-6 Alkyl-SOR e1 、-C 0-6 Alkyl-SO2R e1 、-C 0-6 Alkyl-C(=O)R e1 、-C 0-6 Alkyl-C(=O)NR e1 、-C 0-6 Alkyl-C(=O)OR e1 、-C 0-6 Alkyl-NR e1 R e2 、-C 0-6 Alkyl-NR e1 C(=O)R e2 、-C 0-6 Alkyl-OC(=O)R e1 、-C 0-6 Alkyl-SONR e1 、-C 0-6 Alkyl-SO2NR e1 、-C 0-6 Alkyl-NHS(O)2R e1 、-C 0-6 Alkyl-NHS(O)R e1 、-C 0-6 Alkyl-NR e1 C(=O)OR e2 、-C 0-6 Alkyl-NR e1 C(=O)NR e2 、-C 0-6 Alkyl-(O)(OR e1 )2 and -C0-6 Alkyl-P(O)(R e1 )2.

[0210] "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group, which can be combined with other groups. Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups with 3 to 8 members are preferred. Cycloalkyl groups with 3 to 6 members are more preferred. Cycloalkyl groups with 3 to 4 members are more preferred. Polycyclic hydrocarbon groups include linked, spirocyclic, fused, or bridged cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:

[0211] "Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated π electron system and can be combined with other groups. Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc. Preferably, a 3-8 membered cycloalkenyl. More preferably, a 3-6 membered cycloalkenyl. More preferably, a 5-6 membered cycloalkenyl. Polycyclic cycloalkenyls include linked rings, spiro rings, fused rings, or bridged ring cycloalkenyls. Including but not limited to the following groups:

[0212] The cycloalkyl or cycloalkenyl group may be fused with an aryl, heteroaryl or heterocyclic group, including but not limited to tetrahydronaphthyl and the like.

[0213] "Alkenyl" refers to a linear, branched or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to ethenyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably C 2-6 More preferably C 2-4 Alkenyl.

[0214] "Alkynyl" refers to a linear, branched or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. 2-6 More preferably C 2-4 Alkynyl.

[0215] "Halogen" refers to fluorine, chlorine, bromine or iodine, with fluorine, chlorine and bromine being preferred.

[0216] "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms have been replaced by the same or different halogen atoms, including but not limited to -CH2Cl, -CHF2, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0217] "Alkylamino" refers to NH3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, etc.

[0218] "Dialkylamino" refers to a group having the structure N(C 1-6 The group of alkyl)2 includes but is not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino and the like.

[0219] "Aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or unfused aromatic rings, including but not limited to phenyl, naphthyl, and indenyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. Phenyl or naphthyl is more preferred. Phenyl is most preferred.

[0220] "Heterocyclyl" refers to a 4-12 membered non-aromatic monocyclic or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings with only single bonds and unsaturated rings with at least one double bond (C=C, C=N or N=N), but not forming a completely conjugated π electron system. The heteroatoms are independently selected from N, O, S, nitrogen oxide (NO), sulfoxide, S(O)(=NH) and sulfone. Polycyclic ring systems include fused, bridged or spiro ring systems. Examples of monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc. Preferred are 4-7 membered heterocyclic groups. More preferred are 4-6 membered heterocyclic groups. Examples of polycyclic heterocyclyl moieties include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2 .1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, etc. Examples of unsaturated heterocyclic moieties include, but are not limited to:

[0221] The heterocyclic group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: deuterium atoms, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O), -C 0-6 Alkyl-OR e1 、-C 0-6 Alkyl-SR e1 、-C 0-6 Alkyl-SOR e1 、-C 0-6 Alkyl-SO2R e1 、-C 0-6 Alkyl-C(=O)R e1 、-C 0-6 Alkyl-C(=O)NR e1 、-C 0-6 Alkyl-C(=O)OR e1 、-C 0-6 Alkyl-NR e1 R e2 、-C 0-6 Alkyl-NR e1 C(=O)R e2 、-C 0-6 Alkyl-OC(=O)R e1 、-C 0-6 Alkyl-SONR e1 、-C 0-6 Alkyl-SO2NR e1 、-C 0-6 Alkyl-NHS(O)2R e1 、-C 0-6 Alkyl-NHS(O)R e1 、-C 0-6 Alkyl-NR e1 C(=O)OR e2 、-C 0-6 Alkyl-NR e1 C(=O)NR e2 、-C 0-6 Alkyl-(O)(OR e1 )2 and -C 0-6 Alkyl-P(O)(R e1 )2.

[0222] "Heteroaryl" refers to a substituted or unsubstituted 5- or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or biheteroaromatic ring system containing 1-4 heteroatoms independently selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0223] Heteroaryl is optionally substituted or unsubstituted, and the substituents are preferably one or more of the following groups: deuterium atoms, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 Heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O), -C 0-6 Alkyl-OR e1 、-C 0-6 Alkyl-SR e1 、-C 0-6 Alkyl-SOR e1 、-C 0-6 Alkyl-SO2R e1 、-C 0-6 Alkyl-C(=O)R e1 、-C 0-6 Alkyl-C(=O)NR e1 、-C 0-6 Alkyl-C(=O)OR e1 、-C 0-6 Alkyl-NR e1 R e2 、-C 0-6 Alkyl-NR e1 C(=O)R e2 、-C 0-6 Alkyl-OC(=O)R e1 、-C 0-6 Alkyl-SONR e1 、-C 0-6 Alkyl-SO2NR e1 、-C 0-6 Alkyl-NHS(O)2R e1 、-C 0-6 Alkyl-NHS(O)Re1 、-C 0-6 Alkyl-NR e1 C(=O)OR e2 、-C 0-6 Alkyl-NR e1 C(=O)NR e2 、-C 0-6 Alkyl-(O)(OR e1 )2 and -C 0-6 Alkyl-P(O)(R e1 )2.

[0224] "Bridged ring" refers to a polycyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The ring atoms may be all carbon atoms or one or more ring atoms may be selected from N, O, S, SO or SO2. 7-10 rings are preferred.

[0225] "Spirocyclic" refers to a polycyclic group in which any two rings share a common carbon atom. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or SO2. Preferably, the ring has 5-10 rings.

[0226] Fused ring: refers to a polycyclic group in which each ring shares two adjacent atoms with other rings in the system.

[0227] According to the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group.

[0228] A cyclic group can be bonded to another group in a variety of ways. If the bonding method is not specified, all possible methods are included. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

[0229] "Alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy and other similar groups. 1-8 Alkoxy. More preferably C 1-6 Alkoxy. More preferably C 1-4 Alkoxy.

[0230] "Cycloalkoxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Preferably, C 3-8 Cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and other similar groups.

[0231] "Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxhexyloxy, piperidinyloxy and other similar groups.

[0232] "Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compound of Formula I and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. Examples of organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts. The organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc. Chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds.

[0233] "Prodrug molecule" refers to a prodrug that can be converted into a compound of the present invention and a pharmaceutically acceptable salt thereof in vivo.

[0234] "N-oxide" refers to a compound containing an amine functional group or a heteroaryl compound containing a nitrogen atom, which can be formed by oxidizing one or more nitrogen atoms. + The compound is preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl group containing N.

[0235] "Hydrate" refers to an association formed with a certain amount of water.

[0236] "Solvate" refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.

[0237] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with other chemical components, such as a pharmaceutically acceptable carrier, excipient, or diluent. The purpose of a pharmaceutical composition is to facilitate administration to an animal. Pharmaceutical compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity modifiers, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.

[0238] "Pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, ingredient, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or delivering a compound of the invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that is not unduly toxic or has adverse effects and is suitable for use in contact with animal tissue.

[0239] Some pharmaceutically acceptable carrier substances include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agarose; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Sterile pyrogen-free water; (17) Physiological saline; (18) Ringer's solution; (19) Alcohols, such as ethanol and propanol; (20) Phytophosphate buffer; (21) Other non-toxic substances compatible in pharmaceutical dosage forms, such as acetone.

[0240] Each pharmaceutically acceptable carrier should be compatible with the other components, for example, forming a formulation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs, and with a reasonable benefit-risk ratio.

[0241] The pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The preparation methods and processes of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). DETAILED DESCRIPTION

[0242] The first group of preparation examples: Preparation of intermediates A1-A28

[0243] Intermediate A1. Preparation of 5-((4-((5-iodopyrimidin-4-yl)amino)-2-chlorophenyl)oxy)-1-methyl-1H-benzimidazole

[0244] Step 1: 5-(2-chloro-4-nitrophenoxy)-1-methyl-1H-benzimidazole

[0245] 1-Methyl-1H-benzimidazol-5-ol (1.0 mg, 6.75 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (1.9 g, 13.4 mmol) and 2-chloro-1-fluoro-4-nitrobenzene (1.18 g, 6.75 mmol) were added sequentially and stirred at room temperature for 1 h. The reaction was quenched by the addition of water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel chromatography using a gradient elution of ethyl acetate / petroleum ether (0-76%) to obtain 5-(2-chloro-4-nitrophenoxy)-1-methyl-1H-benzimidazole (yellow solid, 1.8 g, 87.8%). MS (ESI) + )m / z=304.1[M+H] + In this step, potassium carbonate can also be replaced by cesium carbonate or sodium carbonate.

[0246] Step 2: 3-chloro-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline

[0247] 5-(2-Chloro-4-nitrophenoxy)-1-methyl-1H-benzimidazole (1.8 g, 5.9 mmol) was dissolved in a mixture of methanol (10 mL) and water (2 mL). Iron powder (1.6 g, 29.5 mmol) and ammonium chloride (3.2 g, 59.0 mmol) were added sequentially. The atmosphere was replaced with nitrogen and the temperature was raised to 60°C with stirring for 1 h. The reaction mixture was cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was added to water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 3-chloro-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (yellow solid, 1.5 g, 92.5%, crude product). MS (ESI) + )m / z=274.2[M+H] + .

[0248] Step 3. Preparation of 5-((4-((5-iodopyrimidin-4-yl)amino)-2-chlorophenyl)oxy)-1-methyl-1H-benzimidazole

[0249] 3-Chloro-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (500 mg, 1.8 mmol) was dissolved in isopropanol (5 mL), and 5-iodo-4-chloropyrimidine (439 mg, 1.8 mmol) was added. The mixture was heated to 80°C and stirred for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of methanol / dichloromethane (0-10%) to obtain 5-((4-((5-iodopyrimidin-4-yl)amino)-2-chlorophenyl)oxy)-1-methyl-1H-benzimidazole (yellow solid, 400 mg, 45.8%). MS (ESI) + )m / z=478.9[M+H] + .

[0250] Preparation of intermediates A2-A8, A19-A26

[0251] Intermediates A2-A8 and A19-A26 were prepared using commercially available aryl / heteroarylphenols and halogenated aryl / heteroaryl nitro compounds or halogenated heteroaryl and aryl / heteroaryl nitrophenol compounds as raw materials, following the synthesis method for Intermediate A1 (or using 1,4-dioxane as solvent, N,N-diisopropylethylamine or triethylamine as catalyst, and reaction conditions of 60-90°C). See Table 1.

[0252] Table 1 Intermediates A2-A8, A19-A26

[0253] Intermediate A9. Preparation of 5-iodo-6-methyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0254] Dissolve 3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (298.6 mg, 1.2 mmol) in anhydrous ethanol (5 mL), add 4-chloro-5-iodo-6-methylpyrimidine (300 mg, 1.2 mmol) and methanesulfonic acid (11.3 mg, 0.12 mmol), and heat to 70°C with stirring for 1 h. The reaction mixture is cooled to room temperature, quenched by the addition of water (5 mL), and adjusted to alkalinity with sodium bicarbonate. Extract with ethyl acetate (20 mL x 3), and the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using a gradient elution of methanol / dichloromethane = 0-10% as the eluent to obtain 5-iodo-6-methyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (brown oil, 523 mg, 94.1%). MS (ESI + )m / z=472.1[M+H] + .

[0255] Preparation of Intermediate A10 5-bromo-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-4-amine

[0256] 5-Bromo-6-chloropyrimidin-4-amine (500 mg, 2.4 mmol) was dissolved in tert-butanol (8 mL) at 0°C. The atmosphere was replaced with nitrogen, and 3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (607.6 mg, 2.4 mmol) and trifluoroacetic acid (273.5 mg, 2.4 mmol) were added. The mixture was heated to 100°C and stirred for 1 hour. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography using a gradient elution of methanol / dichloromethane (0-10%) to obtain 5-bromo-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-4-amine (yellow solid, 950 mg, 93.1%). MS (ESI) + )m / z=425.0[M+H] + .

[0257] Intermediate A11. 5-Bromo-N 4 Preparation of -(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidine-2,4-diamine

[0258] In a 40 mL microwave tube, 5-bromo-2-chloro-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (Intermediate A6, 500 mg, 1.1 mmol) was added to a mixed solution of aqueous ammonia (2 mL) and 1,4-dioxane (1 mL), stirred evenly, and heated in a microwave to 100°C and stirred for 2 h. Cooled to room temperature, concentrated under reduced pressure to obtain 5-bromo-N 4 -(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidine-2,4-diamine (green solid, 400 mg, crude product). MS (ESI + )m / z=425.2[M+H] + .

[0259] Intermediate A12. 5-Iodo-N 4 -(2-methoxyethyl)-N 6 Preparation of -(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine

[0260] 6-Chloro-5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (Intermediate A5, 300 mg, 0.7 mmol) was dissolved in isopropanol (5 mL), 2-methoxyethylamine (137.5 mg, 1.8 mmol) and triethylamine (185.2 mg, 1.8 mmol) were added, the atmosphere was replaced with nitrogen, and the temperature was raised to 100°C and stirred for 1 h. After cooling to room temperature, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 0-15% as the eluent to obtain 5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine. 4 -(2-methoxyethyl)-N 6 -(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (brown solid, 125 mg, 38.6%). MS (ESI + )m / z=531.1[M+H] + .

[0261] Intermediate A13. Preparation of 5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)-6-methylthiopyrimidin-4-amine

[0262] 6-Chloro-5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (Intermediate A5, 500 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium thiomethoxide (213.7 mg, 3.0 mmol) was added and the mixture was heated to 110°C and stirred for 5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography using 10% methanol / dichloromethane as the eluent to obtain 5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)-6-methylthiopyrimidin-4-amine (pale yellow solid, 450 mg, 87.9%). MS (ESI) + )m / z=504.0[M+H] + .

[0263] Intermediate A14. Preparation of 5-iodo-N-methyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0264] Step 1: N,3-dimethyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline

[0265] 3-Methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (2 g, 7.9 mmol) was dissolved in toluene (40 mL). Paraformaldehyde (0.28 g, 9.48 mmol) and palladium on carbon (0.84 g, 7.9 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was heated to 60°C and stirred for 2 h. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol / dichloromethane (0-10%) as the eluent to afford N,3-dimethyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (off-white solid, 900 mg, 38.4%). MS (ESI) + )m / z=268.2[M+H] + .

[0266] Step 2: 5-iodo-N-methyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0267] 5-Iodo-N-methyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine was prepared using N,3-dimethyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline as the starting material according to the method for synthesizing intermediate A9. MS (ESI + )m / z=472.1[M+H] + .

[0268] Intermediate A15. Preparation of 4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-ol

[0269] 3-Methyl-4-((1-methylbenzimidazol-5-yl)oxy)aniline (1.7 g, 6.9 mmol) was dissolved in acetic acid (20 mL), and 4-chloropyrimidin-5-ol (1.5 g, 11.5 mmol) was added. The mixture was heated to 60°C and stirred for 2 h. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol / dichloromethane = 0-35%) to obtain 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-ol (yellow solid, 800 mg, 20.0%). MS (ESI) + )m / z=348.2[M+H] + .

[0270] Intermediate A16. Preparation of 5-(4-iodo-2-methylphenoxy)-1-methyl-1H-benzimidazole

[0271] 3-Methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (2g, 7.9mmol) was dissolved in acetonitrile (20mL), and cuprous iodide (3.0g, 15.8mmol) was added. tert-Butyl nitrite (1.2g, 11.9mmol) was added at 0°C, and the mixture was warmed to room temperature and stirred for 1h. The reaction was quenched by adding water (20mL) and extracted with ethyl acetate (20mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography (methanol / dichloromethane = 0-50%) to obtain 5-(4-iodo-2-methylphenoxy)-1-methyl-1H-benzimidazole (yellow solid, 600mg, 20.9%). MS (ESI) + )m / z=365.1[M+H] + .

[0272] Intermediate A17. Preparation of 5-bromo-6-difluoromethyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0273] Step 1: 5-Bromo-6-(difluoromethyl)pyrimidin-4-ol

[0274] In a 40 mL single-necked flask, 6-(difluoromethyl)pyrimidin-4-ol (800 mg, 5.5 mmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (1.95 mg, 11.0 mmol) was added under ice-cooling. The atmosphere was replaced with nitrogen, and the temperature was raised to 70°C and stirred for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-80%) as the eluent to obtain 5-bromo-6-(difluoromethyl)pyrimidin-4-ol (yellow solid, 1.2 g, 97.40%). MS (ESI + )m / z=224.9[M+H] + .

[0275] Step 2: 5-Bromo-4-chloro-6-(difluoromethyl)pyrimidine

[0276] To a 40 mL single-necked flask, add 5-bromo-6-(difluoromethyl)pyrimidin-4-ol (1.2 g, 5.3 mmol). Phosphorus oxychloride (10 mL) was slowly added dropwise under ice-cooling. The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C with stirring for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield 5-bromo-4-chloro-6-(difluoromethyl)pyrimidine (yellow oil, 1.2 g, 92.42%, crude product).

[0277] Step 3: 5-bromo-6-difluoromethyl-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0278] 5-Bromo-6-(difluoromethyl)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (yellow solid) was prepared using 5-bromo-4-chloro-6-(difluoromethyl)pyrimidine and 3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)aniline as starting materials according to the third step synthesis method of Intermediate A1. MS (ESI) + )m / z=460.2[M+H] + .

[0279] Intermediate A18. 5-(4-((5-iodopyrimidin-4-yl)oxy)-2-methylphenoxy)-1-methyl-1H-benzo[d]imidazole

[0280] Step 1: 3-Methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenol

[0281] In a 100 mL eggplant flask at 0°C, 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (1 g, 3.9 mmol) was dissolved in 30% concentrated sulfuric acid (10 mL). An aqueous solution of sodium nitrite (409 mg, 5.9 mmol) was added under ice-salt bath. The mixture was stirred at 0°C for 20 min. Then, 10% concentrated sulfuric acid (0.5-1 mL) was slowly added dropwise. The temperature was raised to 100°C and stirred for 1 h. The reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate to pH 7-8. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether = 0-50% as eluent to obtain 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenol (brown solid, 974 mg, 97.0%). MS (ESI + )m / z=255.2[M+H] + .

[0282] Step 2: 5-(4-((5-iodopyrimidin-4-yl)oxy)-2-methylphenoxy)-1-methyl-1H-benzo[d]imidazole

[0283] To a 40 mL reaction bottle at room temperature, 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenol (220 mg, 0.87 mmol), N,N-dimethylformamide (8 mL), cesium carbonate (564 mg, 1.730 mmol) and 4-chloro-5-iodopyrimidine (208 mg, 0.87 mmol) were added in sequence, and the temperature was raised to 90 °C and stirred for 1 h. Water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with water (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using methanol / dichloromethane = 0-10% as eluent to obtain 5-(4-((5-iodopyrimidin-4-yl)oxy)-2-methylphenoxy)-1-methyl-1H-benzo[d]imidazole (brown oil, 360 mg, 90.8%). MS (ESI + )m / z=459.2[M+H] + .

[0284] Intermediate A27. Preparation of N-(4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylphenyl)-5-iodopyrimidin-4-amine

[0285] Step 1: Under nitrogen protection, 7-bromoimidazole [1,2-a] pyridine (2 g, 10.2 mmol) was dissolved in a mixed solution of dimethyl sulfoxide / water (30 mL, 4 / 1 v / v), and lithium hydroxide monohydrate (899.6 mg, 21.4 mmol), N, N'-bis (4-hydroxy-2,6-dimethylphenyl) oxamide (BHMPO, 66.9 mg, 0.2 mmol) and copper acetylacetonate (53.2 mg, 0.2 mmol) were added in sequence. The mixture was heated to 80 ° C and stirred for 2 h. After the reaction was complete, the temperature was lowered to room temperature and water (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane / methanol (3 / 1 v / v, 30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using methanol / dichloromethane (15%) as eluent to obtain imidazo[1,2-a]pyridin-7-ol (yellow oil, 1.0 g, 73.2%). MS (ESI + )m / z=157.1[M+Na+H] + .

[0286] Step 2: Dissolve imidazo[1,2-a]pyridin-7-ol (1.0 g, 7.45 mmol) in N,N-dimethylformamide (20 mL). Add cesium carbonate (4.9 g, 14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g, 7.45 mmol) sequentially. Heat to 80°C and stir for 3 h. After the reaction is complete, cool to room temperature and add water (30 mL). The mixture is extracted with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol / dichloromethane (15%) as the eluent to afford 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (pale yellow solid, 1.1 g, 55.0%). MS (ESI) + )m / z=270.0[M+H] + .

[0287] Step 3: Dissolve 7-(2-methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (1.0 g, 3.71 mmol) in acetonitrile (15 mL) and add N-chlorosuccinimide (595.1 mg, 4.46 mmol). Stir at room temperature for 16 h. After the reaction is complete, add water (30 mL) to the reaction solution, extract the mixture with ethyl acetate (40 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using ethyl acetate / petroleum ether (35%) as the eluent to obtain 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (yellow solid, 360 mg, 31.9%). MS (ESI + )m / z=304.1[M+H] + .

[0288] Steps 4 and 5: Using 3-chloro-7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine as starting material, follow the procedure of Steps 2 and 3 of Intermediate A1 to prepare N-(4-((3-chloroimidazo[1,2-a]pyridin-7-yl)oxy)-3-methylphenyl)-5-iodopyrimidin-4-amine (yellow oil, 250 mg, 55.2%). MS (ESI + )m / z=478.0[M+H] + .

[0289] Intermediate A28. 5-Iodo-N 4 -methyl-N 6 Preparation of -(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine

[0290] Under nitrogen protection, 6-chloro-5-iodo-N-(3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (Intermediate A5, 1 g, 2.03 mmol), n-butanol (10 mL), methylamine hydrochloride (94.7 mg, 3.05 mmol) and N,N-diisopropylethylamine (788.5 mg, 6.10 mmol) were added to a 100 mL reaction bottle in sequence. The temperature was raised to 120°C and stirred for 2 h. After the reaction was complete, the temperature was lowered to room temperature. The reaction solution was slowly poured into water (50 mL) and filtered. The filtrate was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using a gradient elution of dichloromethane / methanol (0-10%) as the eluent to obtain 5-iodo-N 4 -methyl-N 6-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (off-yellow solid, 600 mg, 58.8%). MS (ESI + )m / z=487.0[M+H] + .

[0291] The second group of preparation examples: Preparation of intermediates B1-B22

[0292] Intermediate B1. Preparation of tert-butyl 2-ethynylazetidine-1-carboxylate

[0293] Step 1: tert-Butyl 2-(Hydroxymethyl)azetidine-1-carboxylate

[0294] In a 100 mL single-necked flask, methyl 1-tert-butyloxycarbonyl-azetidine-2-carboxylate (1.0 g, 4.7 mmol) was dissolved in methanol (15 mL). Sodium borohydride (351.5 mg, 9.4 mmol) was added under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched by the addition of water (10 mL) under ice-cooling, and concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (white solid, 700 mg, crude product).

[0295] Step 2: tert-Butyl 2-Formylazetidine-1-carboxylate

[0296] Dissolve tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (3.0 g, 16.0 mmol) in dichloromethane (100 mL), add Dess-Martin periodinane (13.6 g, 32.0 mmol), and stir at room temperature for 1 h. Add aqueous sodium bicarbonate (50 mL) to quench the reaction, filter, and extract the filtrate with dichloromethane (200 mL x 3). The combined organic phases are washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain tert-butyl 2-formylazetidine-1-carboxylate (white solid, 2.4 g, 80.9%).

[0297] Step 3: tert-Butyl 2-ethynylazetidine-1-carboxylate

[0298] To a 250 mL single-necked flask, tert-butyl 2-formylazetidine-1-carboxylate (2.4 g, 13.0 mmol), methanol (10.5 mL), and potassium carbonate (3.6 g, 26.0 mmol) were added sequentially. The atmosphere was replaced with nitrogen, and dimethyl (1-diazo-2-oxo-propanol)-phosphonate (3.7 g, 19.5 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 1 h. Water (20 mL) was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-ethynylazetidine-1-carboxylate (red oil, 3.0 g, crude product).

[0299] Intermediate B2. Preparation of tert-butyl (1-cyclopropylpropyl-2-yn-1-yl)carbamate

[0300] Intermediate B2 was prepared using commercially available methyl 2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetate as raw material and the synthetic method of intermediate B1.

[0301] Intermediate B3. Preparation of tert-butyl (2S)-2-ethynyl-2-methylpyrrolidine-1-carboxylate

[0302] Step 1: (2S)-2-Formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0303] (2S)-2-Methyl-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (500 mg, 2.2 mmol) was dissolved in dichloromethane (10 mL). 4-(Piperidin-1-yl)pyridine (566 mg, 3.5 mmol) and 4-(Piperidin-1-yl)-1-trifluoromethanesulfonylpyridin-1-ium (1.1 g, 3.7 mmol) were added sequentially. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (307.0 mg, 2.4 mmol) was quickly added at room temperature. The atmosphere was replaced with nitrogen and stirred at room temperature for 10 min. After completion of the reaction as monitored by TLC, water (5 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using ethyl acetate / petroleum ether (0-50%) as the eluent by gradient elution to obtain (2S)-2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (colorless transparent liquid, 312 mg, 67.1%). MS (ESI + )m / z=158.2[M-56] + .

[0304] Step 2: (2S)-2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0305] Using (2S)-2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester as starting material, the synthetic method of intermediate B1, step 2, was used to prepare (2S)-2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (yellow oil, 140 mg, 47.2%).

[0306] Preparation of intermediates B4-B16

[0307] Intermediates B4-B16 were prepared using commercially available acid or aldehyde compounds as starting materials using the synthesis method of intermediate B3, as shown in Table 2.

[0308] Table 2 Intermediates B4-B16

[0309] Intermediate B17. Preparation of tert-butyl 2-ethynyl-5-methylpiperidine-1-carboxylate

[0310] Step 1: tert-Butyl 2-formyl-5-methylpiperidine-1-carboxylate

[0311] Dissolve tert-butyl 3-methylpiperidine-1-carboxylate (1.0 g, 5.0 mmol) in tetrahydrofuran (10 mL), replace nitrogen, add N,N,N',N'-tetramethylethylenediamine (874.7 mg, 7.5 mmol) at -78 ° C, slowly add sec-butyllithium (353.6 mg, 5.5 mmol) dropwise, maintain stirring at -78 ° C for 30 min, then add N,N-dimethylformamide (1.0 g, 15.1 mmol) dropwise, stir at -78 ° C for 1 h, add aqueous ammonium chloride solution (10 mL) to quench the reaction, and extract the mixed solution with ethyl acetate (40 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using ethyl acetate / petroleum ether = 0-50% as the eluent by gradient elution to obtain tert-butyl 2-formyl-5-methylpiperidine-1-carboxylate (colorless transparent liquid, 445 mg, 39.0%). MS (ESI + )m / z=172.2[M-56] + .

[0312] Step 2: tert-Butyl 2-ethynyl-5-methylpiperidine-1-carboxylate

[0313] 2-Ethynyl-5-methylpiperidine-1-carboxylic acid tert-butyl ester (yellow oil, 280 mg, 64.0%) was prepared using tert-butyl 2-formyl-5-methylpiperidine-1-carboxylate as starting material according to the synthetic method of intermediate B1, step 2.

[0314] Intermediate B18. Preparation of tert-butyl 2-ethynyl-6-methylpiperidine-1-carboxylate

[0315] Using tert-butyl 2-methylpiperidine-1-carboxylate as starting material, tert-butyl 2-ethynyl-6-methylpiperidine-1-carboxylate (colorless transparent liquid, 398 mg, 81.0%) was prepared according to the synthetic method of intermediate B17.

[0316] Intermediate B19. Preparation of tert-butyl propyl-2-yn-1-yl (2,2,2-trifluoroethyl)carbamate

[0317] Dissolve tert-butyl (2,2,2-trifluoroethyl)carbamate (300 mg, 1.5 mmol) in tetrahydrofuran (5 mL), replace the nitrogen atmosphere, and add sodium hydride (90.4 mg, 3.8 mL) at 0°C. Stir at room temperature for 30 min, then add propargyl bromide (215 mg, 1.8 mmol) dropwise, and stir at room temperature for 3 h. After the reaction is completed, monitor the reaction by TLC, quench the reaction by adding water (5 mL), and extract the mixture with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain tert-butyl propyl-2-yn-1-yl (2,2,2-trifluoroethyl)carbamate (a colorless oil, 280 mg).

[0318] Intermediate B20. Preparation of tert-butyl cyclopropyl(propyl-2-ynyl-1-yl)carbamate

[0319] Cyclopropyl(propyl-2-ynyl-1-yl)carbamic acid tert-butyl ester (colorless oil, 578 mg, 93.1%) was prepared using cyclopropylcarbamic acid tert-butyl ester as starting material according to the synthetic method of intermediate B19. MS (ESI + )m / z=196.2[M+H] + .

[0320] Intermediate B21. tert-Butyl (1-ethynylcyclopropyl)(methyl)carbamate

[0321] Tert-butyl (1-ethynylcyclopropyl)(methyl)carbamate (colorless oil) was prepared from tert-butyl (1-ethynylcyclopropyl)carbamate according to the synthetic method of intermediate B19.

[0322] Intermediate B22. Preparation of tert-butyl (1-phenylpropyl-2-ynyl-1-yl)carbamate

[0323] 1-Phenylprop-2-yn-1-amine (105 mg, 0.8 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (161.9 mg, 1.6 mmol) and di-tert-butyl dicarbonate (349.2 mg, 1.6 mmol) were added. The mixture was stirred at room temperature for 1 h. Water (1 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (6 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain tert-butyl (1-phenylpropyl-2-yn-1-yl)carbamate (pale yellow oil, 135.1 mg, 73.7%). MS (ESI) + )m / z=331.3[M+H] + .

[0324] The third group of preparation examples: Preparation of intermediates C1-C6

[0325] Intermediate C1. Preparation of 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoic acid

[0326] Step 1: (2S)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0327] To a 40 mL reaction flask, triethyl phosphonoacetate (2.3 g, 10.0 mmol), tetrahydrofuran (20 mL), potassium tert-butoxide (3.4 g, 30.1 mmol), and tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (2 g, 10.0 mmol) were added sequentially. The atmosphere was replaced with nitrogen and stirred at room temperature for 6 h. After completion of the reaction as monitored by TLC, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain tert-butyl (2S)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (yellow oil, 2.6 g, 93.3%). MS (ESI) + )m / z=270.5[M+H] + .

[0328] Step 2: Ethyl 3-((2S)-pyrrolidin-2-yl)prop-2-enoate

[0329] To a 50 mL reaction flask, add tert-butyl (2S)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (2.6 g, 9.7 mmol) and a solution of hydrogen chloride in 1,4-dioxane (20 mL). Stir at room temperature for 1 hour. After TLC monitoring, the reaction was complete and concentrated under reduced pressure to yield ethyl 3-((2S)-pyrrolidin-2-yl)prop-2-enoate (yellow oil, 2.0 g, 91.8%, crude product). MS (ESI) + )m / z=170.1[M+H] + .

[0330] Step 3: Ethyl 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoate

[0331] Ethyl 3-((2S)-pyrrolidin-2-yl)prop-2-enoate (1.0 g, 5.9 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (70.9 mg, 3.0 mmol) was added under ice-cooling and stirred for 30 min. Then, iodomethane (838.8 mg, 5.9 mmol) was added to replace the nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by TLC, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel chromatography using ethyl acetate / petroleum ether (0-50%) as the eluent to obtain ethyl 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoate (yellow oil, 279.0 mg, 25.0%).

[0332] Step 4: 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoic acid

[0333] To a 40 mL reaction flask, ethyl 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoate (270 mg, 1.5 mmol), a mixture of tetrahydrofuran / methanol / water (9 mL, 1 / 1 / 1), and lithium hydroxide (35.3 mg, 1.5 mmol) were added sequentially. The atmosphere was replaced with nitrogen and stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue. The pH was adjusted to 2 with HCl solution. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel chromatography using ethyl acetate / petroleum ether (0-50%) as the eluent to obtain 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoic acid (yellow oil, 170 mg, 59.5%). MS (ESI) +)m / z=156.1[M+H] + .

[0334] Intermediate C2. Preparation of 3-(1-methylpyrrolidin-2-yl)prop-2-enoic acid

[0335] 3-(1-Methylpyrrolidin-2-yl)prop-2-enoic acid (yellow oil) was prepared from tert-butyl 2-formylpyrrolidine-1-carboxylate according to the synthetic method of intermediate C1. MS (ESI + )m / z=156.1[M+H] + .

[0336] Preparation of Intermediate C3. 4-(Dimethylamino)but-2-ynoic acid

[0337] Dissolve dimethyl(prop-2-yn-1-yl)amine (400 mg, 4.81 mmol) in tetrahydrofuran (5 mL), cool to -40°C, add n-butyllithium (770.6 mg, 12.0 mmol), and stir for 0.5 h. Dry ice (2.0 g) is then added at this temperature. The mixture is slowly warmed to room temperature and stirred for 0.5 h. The mixture is concentrated under reduced pressure and then lyophilized. The crude product is purified by HPLC (column type: XBridge Prep Amide OBD, 19 mm × 150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 25 mL / min; gradient: 95% to 50% acetonitrile over 8 min; wavelength: 254 / 220 nm) to yield 4-(dimethylamino)but-2-ynoic acid (yellow oil, 100 mg, 16.4%). MS (ESI + )m / z=128.3[M+H] + .

[0338] Intermediate C4. Preparation of 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid

[0339] Dissolve tert-butyl 2-ethynylpyrrolidine-1-carboxylate (500 mg, 2.56 mmol) in tetrahydrofuran (20 mL), cool to -78°C, slowly add n-butyl lithium (196.8 mg, 3.07 mmol), stir at -78°C for 1 hour, then add dry ice and continue stirring for 2 hours. Add water (10 mL) to quench the reaction, and concentrate under reduced pressure to obtain 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (white solid, 650 mg, crude product). MS (ESI) + )m / z=240.2[M+H] + .

[0340] Preparation of intermediates C5-C6

[0341] Intermediates C5-C6 were prepared using commercially available alkynyl compounds as raw materials using the synthesis method of intermediate C4, as shown in Table 3.

[0342] Table 3 Intermediates C5-C6

[0343] The fourth group of preparation examples: Preparation of intermediates D1-D3

[0344] Intermediate D1. Preparation of tert-butyl (2-((4-aminopyrimidin-5-yl)oxy)ethyl)(methyl)carbamate

[0345] Step 1: 2-((tert-Butyloxycarbonyl)(methyl)amino)ethyl methanesulfonate

[0346] Under nitrogen at 0°C, tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.0 g, 5.7 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (1.7 g, 17.1 mmol) was added, followed by the dropwise addition of methylsulfonyl chloride (1.3 g, 11.4 mmol). The mixture was stirred at 0°C for 2 h. The reaction was quenched with water (10 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography using petroleum ether / ethyl acetate (50%) as the eluent to obtain 2-(tert-butoxycarbonyl)(methyl)amino)ethyl methanesulfonate (yellow oil, 1.0 g, 69.2%). MS (ESI) + )m / z=254.1[M+H] + .

[0347] Step 2: tert-Butyl (2-((4-aminopyrimidin-5-yl)oxy)ethyl)(methyl)carbamate

[0348] Under nitrogen, 2-((tert-Butoxycarbonyl)(methyl)amino)ethyl methanesulfonate (1.0 g, 3.9 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (2.6 g, 7.8 mmol) and 4-aminopyrimidin-5-ol (439.0 mg, 3.9 mmol) were added sequentially. The mixture was heated to 60°C and stirred overnight. After cooling to room temperature, the reaction was quenched by the addition of ice water (20 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate (50%) as the eluent to afford tert-butyl (2-((4-aminopyrimidin-5-yl)oxy)ethyl)(methyl)carbamate (yellow oily liquid, 500 mg, 47.2%). MS (ESI) + )m / z=269.1[M+H] + .

[0349] Intermediate D2. Preparation of tert-butyl (3-(4-aminopyrimidin-5-yl)oxy)cyclopentyl)carbamate

[0350] Using tert-butyl (3-hydroxycyclopentyl)carbamate as starting material, tert-butyl (3-(4-aminopyrimidin-5-yl)oxy)cyclopentyl)carbamate (yellow solid, 21.2 g, 94.9%) was prepared according to the synthetic method of intermediate D1. MS (ESI + )m / z=295.1[M+H] + .

[0351] Intermediate D3. Preparation of tert-butyl 3-(((4-aminopyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0352] tert-Butyl 3-(iodomethyl)pyrrolidine-1-carboxylate (1 g, 3.4 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (1.3 g, 10.2 mmol) and 4-aminopyrimidin-5-ol (541.0 mg, 3.4 mmol) were added, and the mixture was heated to 100°C and stirred for 1 h. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel chromatography using petroleum ether / ethyl acetate (0-76%) as the eluent to obtain tert-butyl 3-(((4-aminopyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (yellow solid, 0.9 g, 81.9%). MS (ESI) + )m / z=295.1[M+H] + .

[0353] The fifth group of preparation examples: Preparation of intermediates E1-E11

[0354] Intermediate E1. Preparation of methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0355] Step 1: Ethyl 4-chloropyrimidine-5-carboxylate

[0356] Slowly add thionyl chloride (20 mL) dropwise to a solution of ethyl 4-hydroxypyrimidine-5-carboxylate (5.0 g, 29.7 mmol) in tetrahydrofuran (50 mL), heat to 65°C and stir for 16 h. Cool to room temperature and concentrate under reduced pressure to obtain ethyl 4-chloropyrimidine-5-carboxylate (light yellow solid, 6.0 g, 91.9%). MS (ESI + )m / z=187.0[M+H] + .

[0357] Step 2: Ethyl 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate

[0358] Dissolve 3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (500 mg, 2.0 mmol) in toluene (10 mL). Add 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (155.3 mg, 0.4 mmol), Pd2(dba)3 (180.8 mg, 0.2 mmol), anhydrous potassium phosphate (1.3 g, 6.0 mmol), and ethyl 4-chloropyrimidine-5-carboxylate (552.5 mg, 3.0 mmol) in sequence. Replace the atmosphere with nitrogen, heat to 100°C, and stir for 2 h. Cool the mixture to room temperature, filter, and wash the filter cake with ethyl acetate (100 mL x 3). Concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 0-10% as the eluent to give ethyl 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate (yellow solid, 450 mg, 50.9%). MS (ESI + )m / z=404.1[M+H] + .

[0359] Step 3: 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid

[0360] Ethyl 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate (400 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL) at 0°C. A solution of lithium hydroxide (119 mg, 5.0 mmol) in water (5 mL) was added, and the mixture was stirred at room temperature for 2 h. 1N hydrochloric acid was added to adjust the pH to 2-4, and the mixture was extracted with dichloromethane / methanol = 10 / 1 (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (column type: C18 column, mobile phase: water and acetonitrile, 20%-30% 10 min, wavelength: 254 nm) to give 4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid (yellow solid, 270 mg, 65.3%). MS (ESI + )m / z=376.1[M+H] + .

[0361] Step 4: (4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester

[0362] 4-((3-Methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid (550 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (8 mL) at 0°C. N,N-diisopropylethylamine (946.9 mg, 7.5 mmol), methyl 2-amino-3-hydroxypropanoate hydrochloride (683.8 mg, 4.5 mmol), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 1.1 g, 3.0 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h. The mixture was extracted with dichloromethane / methanol = 10 / 1 (30 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 10% as the eluent to give (4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (yellow solid, 470 mg, 60.6%). MS (ESI + )m / z=477.2[M+H] + .

[0363] Step 5: 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylic acid methyl ester

[0364] Under nitrogen, methyl (4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine ester (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL). Diethylaminosulfur trifluoride (DAST, 101.5 mg, 0.6 mmol) was added at -78°C, and stirred at room temperature for 2 h. After completion of the reaction, water (30 mL) was added at 0°C to quench the reaction. The mixture was extracted with dichloromethane / methanol = 10 / 1 (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 10% as the eluent to give methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylate (yellow solid, 70 mg, 65.5%). MS (ESI + )m / z=459.2[M+H] + .

[0365] Step 6: Methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0366] Under nitrogen, methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylate (110 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL). 1,8-diazobisspiro[5.4.0]undec-7-ene (DBU, 73.1 mg, 0.4 mmol) and bromotrichloromethane (95.1 mg, 0.4 mmol) were added at -78°C. The mixture was warmed to room temperature and stirred for 2 h. Water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane / methanol = 10 / 1 (30 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 10% as the eluent to give methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (yellow solid, 70 mg, 57.5%). MS (ESI + )m / z=457.2[M+H] + .

[0367] Intermediate E2. Preparation of methyl 2-(4-((3-methyl-4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0368] Methyl 2-(4-((3-methyl-4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (yellow solid) was prepared using 3-methyl-4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)aniline and ethyl 4-chloropyrimidine-5-carboxylate as starting materials according to the preparation method of Intermediate E1. MS (ESI + )m / z=444.6[M+H] + .

[0369] Intermediate E3. Preparation of methyl 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazole-4-carboxylate

[0370] Step 1: ethyl 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)aminopyrazolo[1,5-a]pyrimidine-6-carboxylate

[0371] Under nitrogen, 3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (5.1 g, 19.9 mmol) was dissolved in N,N-dimethylformamide (60 mL). N,N-diisopropylethylamine (5.2 g, 40 mmol) and ethyl 7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (3 g, 13.3 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 20% ​​methanol / dichloromethane as the eluent to afford ethyl 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)aminopyrazolo[1,5-a]pyrimidine-6-carboxylate (off-white solid, 5 g). MS (ESI) + )m / z=443.1[M+H] + .

[0372] Step 2: 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0373] Ethyl 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)aminopyrazolo[1,5-a]pyrimidine-6-carboxylate (2 g, 4.5 mmol) was dissolved in ethanol (20 mL) and water (20 mL). Sodium hydroxide (542 mg, 13.6 mmol) was added, and the mixture was heated to 50°C and stirred for 8 h. The mixture was cooled to room temperature, and 1N hydrochloric acid was added to adjust the pH to 2-4. The solvent was removed by concentration under reduced pressure to remove most of the solvent. A white solid precipitated, which was filtered, and the filter residue was washed with ice water and dried to give 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (white solid, 1.6 g). MS (ESI) + )m / z=415.1[M+H] + .

[0374] Step 3: (7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonyl)serine methyl ester

[0375] Dissolve 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.2 g, 2.9 mmol) in N,N-dimethylformamide (60 mL). Add L-threonine methyl ester hydrochloride (1 g, 8.7 mmol) and N,N-diisopropylethylamine (1.1 g, 8.7 mmol). Cool the mixture to 0°C and add N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 3.3 g, 8.7 mmol). Warm the mixture to room temperature and stir for 2 h. Concentrate under reduced pressure. The residue was separated and purified by silica gel chromatography to give (7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonyl)serine methyl ester (yellow solid, 1.8 g). MS (ESI + )m / z=516.2[M+H] + .

[0376] Step 4: 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-4,5-dihydrooxazole-4-carboxylic acid methyl ester

[0377] Methyl (7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonyl)serine (300 mg, 0.6 mmol) was dissolved in dichloromethane (1 mL), 4-dimethylaminopyridine (DMAP, 213 mg, 1.8 mmol) was added, and perfluorobutylsulfonyl fluoride (351 mg, 1.2 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 24 h. Dichloromethane (50 mL) was added to dilute the mixture, and the mixture was washed with aqueous sodium bicarbonate (10 mL) and water (10 mL), respectively. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 20% as the eluent to obtain methyl 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-4,5-dihydrooxazole-4-carboxylate (yellow oil, 190 mg). MS (ESI) + )m / z=498.1[M+H] + .

[0378] Step 5: Methyl 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazole-4-carboxylate

[0379] Methyl 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazole-4-carboxylate (pale yellow solid, 476 mg) was synthesized according to the sixth step of the synthetic intermediate E1 using methyl 2-(7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazole-4-carboxylate as the starting material. MS (ESI) + )m / z=496.1[M+H] + .

[0380] Intermediate E4. Preparation of methyl 5-methyl-2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0381] Under nitrogen, 5-((4-((5-iodopyrimidin-4-yl)amino)-2-methylphenyl)oxy)-1-methyl-1H-benzimidazole (Intermediate A2, 1 g, 2.2 mmol) was dissolved in 1,4-dioxane (20 mL). Pd(OAc)2 (49.1 mg, 0.22 mmol), potassium pivalate (306.6 mg, 2.2 mmol), anhydrous potassium carbonate (604.4 mg, 4.4 mmol), and methyl 5-methyloxazole-4-carboxylate (617.2 mg, 4.4 mmol) were added sequentially. The mixture was heated to 110°C and stirred for 36 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 10% as the eluent to give methyl 5-methyl-2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (pale yellow solid, 200 mg, 19.0%). MS (ESI + )m / z=471.0[M+H] + .

[0382] Intermediate E5. Preparation of ethyl 2-(4-methyl-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0383] Using intermediate A9 and oxazole-4-carboxylic acid ethyl ester as raw materials, 2-(4-methyl-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid ethyl ester (pale yellow solid, 239 mg, 23%) was prepared according to the synthetic method of intermediate E4. MS (ESI + )m / z=485.2[M+H] + .

[0384] Intermediate E6. Preparation of methyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0385] Step 1: Dissolve intermediate A25 (1.4 g, 3.42 mmol) in DMF (30 mL). Add DIEA (1.3 g, 10.25 mmol) and methyl 2-amino-3-hydroxypropionate (610.4 mg, 5.12 mmol) sequentially. Cool to 0°C and slowly add a DMF solution (5 mL) of HATU (2.6 g, 6.8 mmol). Warm to room temperature and stir for 1 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol (10 / 1 v / v, 60 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as the eluent to obtain (4-chloro-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (yellow solid, 1.3 g, 75.0%). MS (ESI + )m / z=511.3[M+H] + .

[0386] Step 2: Dissolve (4-chloro-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (1.4 g, 2.74 mmol) in isopropanol (50 mL) and add p-methoxybenzylamine (563.8 mg, 4.11 mmol). Heat to 60°C and stir for 2 h. After the reaction is complete, cool to room temperature and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as the eluent to afford (4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester as a pale yellow solid, 1.3 g, 81.0%. MS (ESI) + )m / z=612.4[M+H] + .

[0387] Steps 3 and 4: Starting from methyl (4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate, methyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (light yellow solid, 620 mg, 57.0%) was prepared according to the procedure of Steps 5 and 6 of Synthesis of Intermediate E1. MS (ESI) + )m / z=592.3[M+H] + .

[0388] Intermediate E7. Preparation of ethyl 2-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0389] Step 1: Dissolve 5-bromo-4-chloropyrimidine (10.0 g, 51.70 mmol) in N,N-dimethylformamide (100 mL) and add sodium thiomethoxide (4.3 g, 62.04 mmol). Stir at room temperature for 12 h. After the reaction is complete, add water (100 mL) to the reaction solution, extract the mixture with ethyl acetate (200 mL × 3). The combined organic phases are washed with a saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is separated by silica gel column chromatography using ethyl acetate / petroleum ether (40%) as the eluent to afford 5-bromo-4-(methylthio)pyrimidine (pale yellow oil, 6 g, 56.6%). MS (ESI +)m / z=207.0[M+H] + .

[0390] Step 2: Under nitrogen, 5-bromo-4-(methylthio)pyrimidine (5.0 g, 24.38 mmol) was dissolved in 1,4-dioxane (70 mL). Pd(dppf)Cl2 (5.4 g, 7.31 mmol), bis-pinacol borate (18.6 g, 73.15 mmol), and potassium acetate (12.0 g, 121.91 mmol) were added sequentially. The temperature was raised to 90°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 4-methylthio-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (brown solid, 6 g, crude product). MS (ESI) + )m / z=253.3[M+H] + .

[0391] Step 3: Under nitrogen, dissolve 4-methylthio-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (6.0 g, 23.80 mmol) in a mixture of 1,4-dioxane and water (4 / 1 v / v, 62.5 mL). Add Xphos Pd G3 (2.0 g, 2.38 mmol), Xphos (1.1 g, 2.38 mmol), potassium carbonate (8.2 g, 59.49 mmol), and ethyl 2-bromo-1,3-oxazole-4-carboxylate (5.2 g, 23.80 mmol) in sequence. Heat to 80°C and stir for 3 h. After the reaction was complete, the mixture was cooled to room temperature and water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (50%) as the eluent to obtain ethyl 2-(4-(methylthio)pyrimidin-5-yl)oxazole-4-carboxylate (pale yellow solid, 2 g, 31.7%). MS (ESI + )m / z=266.0[M+H] + .

[0392] Step 4: Dissolve ethyl 2-(4-(methylthio)pyrimidin-5-yl)oxazole-4-carboxylate (1.1 g, 4.15 mmol) in dichloromethane (15 mL), cool to 0°C, and add sulfonyl chloride (1.1 g, 8.29 mmol). Stir at 0°C for 0.5 h. After the reaction is complete, warm to room temperature and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using petroleum ether (100%) as the eluent to obtain ethyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate (pink solid, 1.2 g, crude product). MS (ESI + )m / z=254.0[M+H] + .

[0393] Step 5: Dissolve ethyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate (473.4 mg, 1.87 mmol) in isopropanol (20 mL) and add intermediate F4 (359.5 mg, 1.33 mmol). Heat to 90°C and stir for 1 h. After the reaction is complete, cool to room temperature and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as the eluent to afford ethyl 2-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (yellow solid, 625 mg, 68.5%). MS (ESI) + )m / z=489.3[M+H] + .

[0394] Preparation of intermediates E8-E10.

[0395] Intermediates E8-E10 were prepared using ethyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate or methyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate and intermediates F1-F9 as starting materials, following the method for synthesizing intermediate E7, as shown in Table 4.

[0396] Table 4 Intermediates E8-E10

[0397] Intermediate E11. Preparation of ethyl 2-(4-((3-chloro-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate

[0398] Step 1: In a 100 mL reaction flask, ethyl 2-(4-(methylthio)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylate (384.0 mg, 1.45 mmol) was dissolved in dichloromethane (40 mL). m-Chloroperbenzoic acid (mCPBA, 3.40 mmol) was added and stirred at room temperature for 1.5 h. After the reaction was complete, sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (5 mL) were added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 2-(4-(methylsulfonyl)pyrimidin-5-yl)oxazole-4-carboxylate (pale yellow solid, 228.0 mg, 63.0%). MS (ESI + )m / z=298.1[M+H] + .

[0399] Step 2: 2-(4-((3-chloro-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (Intermediate E11, yellow solid, 180 mg, 12.0%) was prepared from ethyl 2-(4-(methylsulfonyl)pyrimidin-5-yl)oxazole-4-carboxylate (200 mg, 2.24 mmol) and 3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate F6) according to the procedure of Step 5 of Intermediate E7. MS (ESI) + )m / z=491.2[M+H] + .

[0400] The sixth group of preparation examples: Preparation of intermediates F1-F9

[0401] Preparation of intermediates F1-F7.

[0402] Intermediates F1-F7 were prepared using commercially available 1-methyl-1H-benzimidazol-5-ol and substituted nitrobenzene compounds as raw materials using the first and second steps of Intermediate A1, as shown in Table 5.

[0403] Table 5 Intermediates F1-F7

[0404] Intermediate F8. Preparation of 3-chloro-4-((7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline

[0405] Step 1: Under nitrogen, 5-bromo-1,2-difluoro-3-nitrobenzene (2.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL). N,N-diisopropylethylamine (4.3 g, 33.61 mmol) and methylamine hydrochloride (2.8 g, 42.02 mmol) were added sequentially. The temperature was raised to 60°C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to afford 4-bromo-2-fluoro-N-methyl-6-nitroaniline (yellow solid, 2.0 g, 95.6%). MS (ESI) + )m / z=249.0[M+H] + .

[0406] Step 2: 4-Bromo-2-fluoro-N-methyl-6-nitroaniline (1.8 g, 7.23 mmol) was dissolved in a mixture of tetrahydrofuran and water (5 / 1 v / v, 24 mL), and iron powder (4.0 g, 72.28 mmol) and ammonium chloride (3.9 g, 72.28 mmol) were added in sequence. The temperature was raised to 60°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (0-100%) as the eluent gradient elution to obtain 4-bromo-6-fluoro-N-methyl-6-nitroaniline. 1 -Methyl-1,2-phenylenediamine (brown oil, 1.1 g, 69.5%). MS (ESI + )m / z=219.0[M+H] + .

[0407] Step 3: Under nitrogen protection, 4-bromo-6-fluoro-N 1 1,2-Methyl-1,2-phenylenediamine (1.1 g, 5.02 mmol) was dissolved in toluene (20 mL) and cooled to 0°C. p-Toluenesulfonamide (86.0 mg, 0.50 mmol) and triethyl orthoformate (1.5 g, 10.04 mmol) were added sequentially. The temperature was raised to 120°C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-10%) to afford 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole (brown solid, 1.1 g, 95.6%). MS (ESI) +)m / z=228.9[M+H] + .

[0408] Step 4: Under nitrogen, dissolve 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole (1.0 g, 4.37 mmol) in a mixture of dimethyl sulfoxide and water (4 / 1 v / v, 10 mL). Add Cu(acac)2 (114.3 mg, 0.44 mmol) and BHMPO (143.4 mg, 0.44 mmol) sequentially. Then slowly add lithium hydroxide monohydrate (769.4 mg, 18.34 mmol). Heat to 80°C and stir for 2 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-20%) as the eluent to give 7-fluoro-1-methyl-1H-benzo[d]imidazol-5-ol (light brown solid, 650 mg, 89.7%). MS (ESI + )m / z=167.1[M+H] + .

[0409] Steps 5 and 6: Using 7-fluoro-1-methyl-1H-benzo[d]imidazol-5-ol and 2-chloro-1-fluoro-4-nitrobenzene as starting materials, 3-chloro-4-((7-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (yellow solid, 450 mg, 90.2%) was prepared according to the procedures of Intermediate A1, Steps 1 and 2. MS (ESI) + )m / z=291.9[M+H] + .

[0410] Intermediate F9. Preparation of 4-(imidazo[1,2-c]pyrimidin-7-yloxy)-3-methylaniline

[0411] Step 1: Under nitrogen, 7-chloroimidazo[1,2-c]pyrimidine (500.0 mg, 3.26 mmol) was dissolved in acetonitrile (8 mL). Potassium carbonate (900.0 mg, 6.51 mmol) and 2-methyl-4-nitrophenol (598.3 mg, 3.91 mmol) were added. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-33%) to afford 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-c]pyrimidine (yellow solid, 180 mg, 20.4%). MS (ESI) + )m / z=271.1[M+H] + .

[0412] Step 2: Dissolve 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-c]pyrimidine (170.0 mg, 0.63 mmol) in a mixture of methanol and water (3 / 1 v / v, 4 mL). Add iron powder (281.1 mg, 5.03 mmol) and ammonium chloride (269.2 mg, 5.03 mmol) sequentially. Heat to 80°C and stir for 2 h. After the reaction is complete, cool to room temperature and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-18%) to afford 4-(imidazo[1,2-c]pyrimidin-7-yloxy)-3-methylaniline (yellow solid, 120 mg, 79.4%). MS (ESI) + )m / z=241.0[M+H] + .

[0413] Preparation Example 7: Preparation of Intermediate G1

[0414] Preparation of Intermediate G1 (tert-Butyl 1-((4-chloropyrimidin-5-yl)ethynyl)cyclopropyl)carbamate

[0415] 4-Chloro-5-iodopyrimidine (1.0 g, 4.16 mmol) was dissolved in N,N-dimethylformamide (10 mL). Pd(PPh3)2Cl2 (291.9 mg, 0.42 mmol), cuprous iodide (79.2 mg, 0.42 mmol), triethylamine (4.2 g, 41.59 mmol), and tert-butyl N-(1-ethynylcyclopropyl)carbamate (753.8 mg, 4.16 mmol) were added sequentially. The mixture was heated to 60°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to obtain a yellow solid (1.2 g, 98.2%). MS (ESI + )m / z=294.1[M+H] + .

[0416] Preparation Example 8: Preparation of Final Product

[0417] Example 1. Preparation of 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one (Final Product 1)

[0418] Step 1: tert-Butyl 2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidine-1-carboxylate

[0419] Under nitrogen, 5-((4-((5-bromopyrimidin-4-yl)amino)-2-methylphenyl)oxy)-1-methyl-1H-benzimidazole (Intermediate A3, 200 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (10 mL). 2-Ethynylazetidine-1-carboxylic acid tert-butyl ester (Intermediate B1, 457.4 mg, 2.5 mmol), cuprous iodide (1.0 mg, 0.005 mmol), bistriphenylphosphine palladium dichloride (35.4 mg, 0.05 mmol), and triethylamine (1.15 g, 1.5 mmol) were added sequentially. The mixture was heated to 100°C and stirred for 1 h. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using ethyl acetate / petroleum ether = 0-50% as eluent to obtain tert-butyl 2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidine-1-carboxylate (yellow liquid, 180 mg, 35.8%). MS (ESI + )m / z=511.4[M+H] + .

[0420] Step 2: 5-(azetidin-2-ylethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0421] Tert-butyl 2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidine-1-carboxylate (200 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5-(azetidin-2-ylethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (yellow liquid, 80 mg, 39.9%, crude product). MS (ESI) + )m / z=411.2[M+H] + .

[0422] Step 3: 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one

[0423] Dissolve 5-(azetidin-2-ylethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (80 mg, 0.2 mmol) in tetrahydrofuran (15 mL). Add triethylamine (59.2 mg, 0.6 mmol). The mixture is cooled to 0°C and acrylic anhydride (22.1 mg, 0.2 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 1 hour. After completion of the reaction, water (20 mL) is added to quench the reaction. The mixture is extracted with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high pressure reverse phase preparative chromatography (column type: XSelect CSH Fluoro Phenyl, 19 mm × 250 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 60 mL / min; gradient: 50%-75% acetonitrile 7 min; wavelength: 254 nm) to obtain 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one.

[0424] White solid, MS (ESI + )m / z=465.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.31(s,2H),8.00(s,1H),7.78(s,1H),7.71(d,J=8.4Hz,1H),7.40-7.29 (m,2H),7.08(d,J=8.8Hz,1H),6.88(d,J=8.8Hz,1H),6.39(d,J=16.8Hz,1H),6.27-6.16(m,1H),5.81-5.73 (m,1H),5.31-5.23(m,1H),4.44-4.25(m,2H),3.88(s,3H),2.82-2.73(m,1H),2.63-2.50(m,1H),2.29(s,3H).

[0425] The condensation method in this step also includes: 1) using a commercially available ene / yne acid compound or intermediate C1-C6 as a raw material, EDCI as a catalyst, pyridine as a solvent, and reacting at room temperature; 2) using an ene / yne acid chloride compound as a raw material, triethylamine as a catalyst, THF as a solvent, and reacting at room temperature.

[0426] Preparation of Example 2-75 Final Products 2-25, 27-29, 31-32, 34-36, 38-41, 43, 47, 49-51, 54, 57, 60-61, 63-66, 68-73, 76-77, 79-80, 124-125, 133, 138-139, 143-144, 152-153, 158-163

[0427] The preparation method of the final product 1 was adopted, and the intermediates A1-A28, intermediates B1-B22, intermediates C1-C6 or commercially available alkynyl compounds and other commercially available compounds were used as raw materials to prepare the final products 2-25, 27-29, 31-32, 34-36, 38-41, 43, 47, 49-51, 54, 57, 60-61, 63-66, 68-73, 76-77, 79-80, 124-125, 133, 138-139, 143-144, 152-153, 158-163, as shown in Table 6.

[0428] Table 6 Final products 2-25, 27-29, 31-32, 34-36, 38-41, 43, 47, 49-51, 54, 57, 60-61, 63-66, 68-73, 76-77, 79-80, 124-125, 133, 138-139, 143-144, 152-153, 158-163

[0429] Example 76. Preparation of (R,Z)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide and (R,E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide (Final Product 30)

[0430] Step 1: (R,Z / E)-tert-Butyl 2-(2-fluoro-3-((3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)amino)-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate

[0431] 5-(3-Aminopropyl-1-ynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (prepared using Intermediate A3 according to the methods of Steps 1 and 2 in Example 1) (120 mg, 0.3 mmol) was dissolved in pyridine (14 mL). (R)-3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-fluoroprop-2-enoic acid (121.4 mg, 0.45 mmol) was added. The mixture was cooled to 0°C and phosphorus oxychloride (95.7 mg, 0.6 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. Aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using methanol / dichloromethane = 0-20% as the eluent to give tert-butyl (R,Z / E)-2-(2-fluoro-3-((3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)amino)-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate (yellow oil, 70 mg, 35.0%). MS (ESI) + )m / z=626.5[M+H] + .

[0432] Step 2: (R,Z / E)-2-Fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)-3-(pyrrolidin-2-yl)acrylamide

[0433] Tert-butyl (R,Z / E)-2-(2-fluoro-3-((3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)amino)-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate (60 mg, 0.09 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.2 mL) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (R,Z / E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)-3-(pyrrolidin-2-yl)acrylamide (yellow oil, 66 mg, crude product). MS (ESI + )m / z=526.4[M+H] + .

[0434] Step 3: (R,Z)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide and (R,E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide

[0435] (R,Z / E)-2-Fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-ynyl-1-yl)-3-(pyrrolidin-2-yl)acrylamide (60 mg, 0.1 mmol) was dissolved in methanol (5 mL). Aqueous formaldehyde solution (37 wt%, 90 mg, 1.14 mmol) was added and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (120.9 mg, 0.5 mmol) was added portionwise and stirred at room temperature for 4 h. The reaction was quenched by adding sodium bicarbonate solution (20 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-pressure preparative column separation (column type: Xselect CSH C18 OBD) Column, 30 mm × 150 mm, 5 μm; mobile phase: water (0.1% formic acid) / acetonitrile; flow rate: 60 mL / min; gradient: 5%-20% acetonitrile 10 min; wavelength: 254 / 220 nm) to obtain (R, Z)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-yl)-1,2-dihydro-2-nitro-4-nitro-2-nitro-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-yl)-1,2-dihydro-2-nitro-4-nitro-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-yl)-1,2-dihydro-2-nitro-1-nitro-2 ...1 The final products 30A and 30B were prepared by mixing (R,E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide (final product 30B). It was not determined whether the final products 30A and 30B specifically corresponded to the cis (Z) configuration or the trans (E) configuration.

[0436] Final product 30A

[0437] Off-white solid, MS (ESI + )m / z=540.2[M+H] + . 1H NMR(500MHz,CD3OD)δ8.49(s,1H),8.32(s,1H),8.13(s,1H),7.67(s,1H),7.56(d,J=8 .7Hz,1H),7.52(d,J=2.5Hz,1H),7.16-7.01(m,2H),6.89(d,J=8.7Hz,1H),6.18-6.01( m,1H),4.40(s,2H),3.93(s,3H),3.80-3.75(m,1H),3.41-3.34(m,1H),2.80-2.71(m,1 H),2.57(s,3H),2.29(s,3H),2.28-2.20(m,1H),2.09-1.95(m,2H),1.85-1.72(m,1H).

[0438] Final product 30B

[0439] Off-white solid, MS (ESI + )m / z=540.2[M+H] + . 1 H NMR(500MHz,CD3OD)δ8.55(s,1H),8.31(s,1H),8.14(d,J=2.5Hz,1H),7.73(s,1H),7.63 (d,J=8.7Hz,1H),7.57(d,J=8.4Hz,1H),7.24-7.11(m,2H),6.95(d,J=8.7Hz,1H),5.91-5 .83(m,1H),4.78-4.60(m,1H),4.43(s,2H),3.98(s,3H),3.56-3.43(m,1H),2.82-2.69( m,1H),2.69-2.57(m,3H),2.38(s,3H),2.30(s,1H),2.01(d,J=32.8Hz,2H),1.81(s,1H).

[0440] Example 77. Preparation of (R,Z / E)-2-fluoro-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(pyrrolidin-2-yl)prop-2-en-1-one (Final Product 52)

[0441] (R,Z / E)-2-Fluoro-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(pyrrolidin-2-yl)prop-2-en-1-one) was prepared using N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)-5-(piperidin-2-ylethynyl)pyrimidin-4-amine as starting material according to the method for synthesizing the final product 30.

[0442] White solid, MS (ESI + )m / z=594.2[M+H] + . 1 H NMR(500MHz, CDCl3)δ8.68(s,1H),8.42(s,2H),7.89(s,1H),7.63-7.22(m, 4H),7.11-7.03(m,1H),6.88(d,J=8.7Hz,1H),5.91-5.54(m,2H),3.87(s,3 H),3.55-3.17(m,3H),3.17-3.00(m,1H),2.59-2.39(m,3H),2.34(s,4H),2 .27-1.99(m,5H),1.98-1.65(m,3H),1.61-1.51(m,1H),1.38-1.30(m,1H).

[0443] Example 78. Preparation of (2E)-N-(1-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-4-morpholinobut-2-enamide (Final Product 33)

[0444] Step 1: (2E)-4-Bromo-N-(1-((4-((3-methyl-4-(1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-enamide

[0445] 5-((1-aminocyclopropyl)ethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (prepared using Intermediate A2 according to the methods of Steps 1 and 2 in Example 1) (164.2 mg, 0.4 mmol) was dissolved in tetrahydrofuran (3 mL), and (2E)-4-bromobut-2-enoyl chloride (145.1 mg, 0.8 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (2E)-4-bromo-N-(1-((4-((3-methyl-4-(1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-enoamide (brown oil, 400 mg, crude product). MS (ESI) + )m / z=557.3[M+H] + .

[0446] Second step: (2E)-N-(1-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-4-morpholinobut-2-enamide

[0447] (2E)-4-Bromo-N-(1-((4-((3-methyl-4-(1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-enamide (446 mg, 0.8 mmol) was dissolved in acetonitrile (4 mL). Morpholine (104.5 mg, 1.2 mmol) and potassium carbonate (331.7 mg, 2.4 mmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 60°C and stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high-pressure preparative chromatography (column type: YMC-Actus Triart C18 ExRS, 30×150 mm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 60 mL / min; gradient: 26%-46% acetonitrile in 10 min; wavelength: 254 / 220 nm) to obtain (2E)-N-(1-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-4-morpholinobut-2-enamide.

[0448] White solid, MS (ESI + )m / z=564.4[M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.66(s,1H),8.55(s,1H),8.30(s,1H),8.17(s,1H),7 .80(s,1H),7.72-7.64(m,1H),7.56(d,J=8.7Hz,1H),7.09(d,J=2.2Hz,1H),7.03-6.95(m, 1H),6.84(d,J=8.7Hz,1H),6.75-6.62(m,1H),6.05(d,J=15.6Hz,1H),3.84(s,3H),3.49(t ,J=4.6Hz,4H),3.09-3.00(m,2H),2.33-2.21(m,7H),1.41-1.26(m,2H),1.26-1.11(m,2H).

[0449] Example 79. Preparation of 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)prop-2-yn-1-one (Final Product 53)

[0450] Step 1: 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one

[0451] Under nitrogen protection, N-(3-methyl-4-((1-methyl-1H-benzimidazole-5-oxy)phenyl)-5-(piperidin-2-ylethynyl)pyrimidin-4-amine (150 mg, 0.3 mmol) was dissolved in pyridine (3 mL), and 3-(trimethylsilyl)prop-2-ynoic acid (43.8 mg, 0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 131.1 mg, 0.6 mmol) were added and the mixture was stirred at room temperature. The mixture was stirred for 1 h. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at low temperature to obtain 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one (brown oil, 200 mg, crude product). MS (ESI) + )m / z=563.4[M+H] + .

[0452] Step 2: 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)prop-2-yn-1-one

[0453] Dissolve 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one (100 mg, 0.2 mmol) in tetrahydrofuran (3 mL). Add triethylamine trihydrofluoride (171.9 mg, 1.2 mmol) and stir at room temperature for 1 h. After completion of the reaction, quench the reaction with water (5 mL) and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue was separated and purified by high pressure preparative column chromatography (column type: XBridge Prep OBD C18 Column, 30 mm × 150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 33%-47% acetonitrile in 10 min; wavelength: 254 / 220 nm) to obtain 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)prop-2-yn-1-one.

[0454] Pale yellow solid, MS (ESI + )m / z=491.3[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.74(s,1H),8.49(d,J=13.8Hz,2H),8.17(s,1H),7.5 6(d,J=8.7Hz,1H),7.49(s,1H),7.41-7.32(m,1H),7.08(d,J=2.3Hz,1H),7.0 2-6.96(m,1H),6.88-6.79(m,1H),5.79-5.66(m,1H),4.35-4.16(m,1H),3.83 (s,3H),3.08-2.93(m,1H),2.22(s,3H),2.12-1.89(m,2H),1.86-1.66(m,4H).

[0455] Example 80. Preparation of N-(1-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-ynamide (Final Product 58)

[0456] Step 1: Dissolve 3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (Intermediate F2, 200.0 mg, 0.69 mmol) in tert-butanol (5 mL). Add tert-butyl (1-((4-chloropyrimidin-5-yl)ethynyl)cyclopropyl)carbamate (Intermediate G1, 201.4 mg, 0.69 mmol), hydrochloric acid, and a mixture of 1,4-dioxane (25.0 mg, 0.69 mmol). Warm to 70°C and stir for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the pH was adjusted to alkaline with sodium bicarbonate solution. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using methanol / dichloromethane (0-15%) as eluent to give tert-butyl (1-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)carbamate (pale yellow solid, 150 mg, 39.9%). MS (ESI + )m / z=549.1[M+H] + .

[0457] Step 2: Tert-butyl (1-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)carbamate (150.0 mg, 0.27 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (3 / 1 v / v, 4 mL) and stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, the pH was adjusted to alkaline with sodium bicarbonate, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-((1-aminocyclopropyl)ethynyl)-N-(3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine as a pale yellow solid, 200 mg, crude. MS (ESI) + )m / z=449.2[M+H] + .

[0458] Step 3: Dissolve 5-((1-aminocyclopropyl)ethynyl)-N-(3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (207.0 mg, 0.46 mmol) in pyridine (5 mL). Add EDCI (176.8 mg, 0.92 mmol) and 2-butynoic acid (19.4 mg, 0.23 mmol) sequentially. Stir at room temperature for 0.5 h. After the reaction was complete, water (30 mL) was added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by high pressure preparative liquid chromatography (column type: Kinetex EVO C18 Column, 21.2×250 mm, 5 μm; mobile phase: acetonitrile / water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient: 28-53-11 min; wavelength: 254 / 220 nm) to obtain N-(1-((4-((3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)but-2-ynamide.

[0459] White solid, MS (ESI + )m / z=515.2[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.25(s,1H),8.59(s,1H),8.47(s,1H),8.35(s,1H),8.25(s,1H),7.66(d,J=8.7Hz,1H),7.46(t,J=8.9Hz,1H),7.35 (d,J=2.3Hz,1H),7.11(dd,J=8.7,2.3Hz,1H),6.75(dd,J=9.0,1.8Hz,1H),3.87(s,3H),1.96(s,3H),1.44-1.34(m,2H),1.19-1.08(m,2H).

[0460] Examples 81-83. Preparation of Final Products 145, 150, 151

[0461] The preparation method of final product 58 was adopted, and intermediates F1-F9, intermediate G1 or commercially available compounds were used as raw materials to prepare final products 145, 150, and 151, as shown in Table 7.

[0462] Table 7 Final products 145, 150, 151

[0463] Example 84. Preparation of 1-(2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one (Final Product 67)

[0464] Step 1: tert-Butyl 2-((2-chloro-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate

[0465] Using intermediate A7 and an alkyne compound as starting materials, tert-butyl 2-((2-chloro-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate (light green solid, 350 mg, 96.2%) was prepared according to the first step of the synthesis method in Example 1. MS (ESI + )m / z=559.4[M+H] + .

[0466] Step 2: tert-Butyl 2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate

[0467] Under nitrogen, tert-butyl 2-((2-chloro-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in a 4 / 1,5 mL ethanol / water mixture. N,N'-dimethyl-1,2-cyclohexanediamine (15.3 mg, 0.11 mmol), sodium azide (58.1 mg, 0.9 mmol), sodium ascorbate (71.2 mg, 0.36 mmol), and copper sulfate pentahydrate (44.7 mg, 0.18 mmol) were added. The mixture was heated to 80°C and stirred for 1 h. After cooling to room temperature, the reaction was quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 0-20% as the eluent to give tert-butyl 2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate (white solid, 96 mg, 99.5%). MS (ESI + )m / z=540.3[M+H]+ .

[0468] Steps 3 and 4. Preparation of 1-(2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0469] Using tert-butyl 2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate as a raw material, 1-(2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one was prepared according to the second and third steps of the synthesis method in Example 1.

[0470] White solid, MS (ESI + )m / z=494.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=15.4Hz,1H),8.23(s,2H),7.65(d,J=8.5Hz,1 H),7.37(s,1H),7.31-7.22(m,1H),7.10(d,J=8.9Hz,1H),6.89-6.81(m,2H),6.2 5(s,1H),6.18-6.08(m,2H),5.76(s,1H),5.00-4.94(m,1H),3.87(s,2H),3.17( d,J=5.2Hz,2H),2.39-2.30(m,1H),1.80(s,1H),1.24(s,5H),0.91-0.80(m,2H).

[0471] Example 85. Preparation of N-((2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide (Final Product 81)

[0472] Step 1: (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methanol

[0473] Under nitrogen protection, methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (60 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to -78 °C, lithium aluminum hydride (10.0 mg, 0.2 mmol) was added, and the temperature was raised to room temperature and stirred for 3 h. Water (10 mL) was added at 0°C to quench the reaction. The mixture was extracted with dichloromethane / methanol (10 / 1, 30 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methanol (yellow solid, 60 mg, 95.9%). MS (ESI + )m / z=429.1[M+H] + .

[0474] Step 2: 5-(4-(azidomethyl))oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0475] Under nitrogen, a 40 mL single-necked flask was charged with (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methanol (60 mg, 0.1 mmol), N,N-dimethylformamide (4 mL), carbon tetrachloride (1 mL), triphenylphosphine (183.7 mg, 0.5 mmol), and sodium azide (45.5 mg, 0.5 mmol) in sequence. The temperature was raised to 90°C and stirred for 24 h. The mixture was cooled to room temperature and quenched with water (20 mL) at 0°C. The reaction was extracted with dichloromethane / methanol (10 / 1; 30 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol / dichloromethane = 10% as the eluent to give 5-(4-(azidomethyl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (yellow solid, 30 mg, 63.5%). MS (ESI + )m / z=454.2[M+H] + .

[0476] Step 3: 5-(4-(aminomethyl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine

[0477] 5-(4-(Azidomethyl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL), and triphenylphosphine (34.7 mg, 0.14 mmol) and water (0.1 mg, 0.007 mmol) were added. The mixture was heated to 60°C and stirred for 2 h. After cooling to room temperature, the filtrate was concentrated under reduced pressure. The residue was separated and purified by thin-layer chromatography using methanol / dichloromethane = 10% as the eluent to give 5-(4-(aminomethyl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (yellow oil, 23 mg, 81.3%). MS (ESI) + )m / z=428.2[M+H] + .

[0478] Step 4: N-((2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide

[0479] Using 5-(4-(aminomethyl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine and acrylic anhydride as raw materials, N-((2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide was prepared according to the method of the third step of Example 1.

[0480] White solid, MS (ESI + )m / z=482.2[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.86(s,1H),8.95(s,1H),8.73(s,1H),8.69(s,1H ),8.19(d,J=13.2Hz,2H),7.71-7.62(m,2H),7.57(d,J=8.8Hz,1H),7.09(s ,1H),7.02-6.96(m,1H),6.92-6.86(m,1H),6.39-6.22(m,1H),6.21-6.10( m,1H),5.69-5.60(m,1H),4.43(d,J=5.8Hz,2H),3.84(s,3H),2.26(s,3H).

[0481] Preparation of Examples 86-95 Final Products 82, 83, 88-90, 96, 102, 104, 165-166

[0482] The preparation method of the final product 81 was adopted, and the intermediates E1-E11 were used as raw materials to prepare the final products 82, 83, 88-90, 96, 102, 104, 165-166, as shown in Table 8.

[0483] Table 8 Final products 82, 83, 88-90, 96, 102, 104, 165-166

[0484] Example 96. Preparation of N-(1-(2-(4-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethyl)acrylamide (Final Product 87)

[0485] Step 1: (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)formaldehyde

[0486] (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methanol (500.0 mg, 1.16 mmol) was dissolved in dichloromethane (50 mL), cooled to 0°C, and Dess-Martin periodinane (DMP, 959.9 mg, 2.33 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with water (100 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used directly in the next step without purification. MS (ESI + )m / z=427[M+H] + .

[0487] Step 2: (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethanol

[0488] Under nitrogen, a 40 mL reaction flask was added with (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)carbaldehyde (374.0 mg, 0.87 mmol) and dry tetrahydrofuran (20 mL). The mixture was cooled to 0°C and a solution of dimethylmagnesium bromide (2M, 209.0 mg, 1.75 mmol) in tetrahydrofuran was added dropwise. The mixture was heated to room temperature and stirred for 2 h. Methanol (1 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column using methanol / dichloromethane = 0%-20% as the eluent to obtain (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethanol as a pale yellow solid, 284.0 mg, 73%). MS (ESI) + )m / z=443[M+H] + .

[0489] Step 3, Step 4 and Step 5: N-(1-(2-(4-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethyl)acrylamide

[0490] N-(1-(2-(4-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethyl)acrylamide was prepared from (2-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethanol according to the second, third and fourth steps of the final product 81.

[0491] White solid, MS (ESI + )m / z=496.2[M+H] + . 1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.95(s,1H),8.73(s,1H),8.59(d,J=8.2Hz,1H), 8.23(s,1H),8.17(s,1H),7.70-7.60(m,2H),7.57(d,J=8.7Hz,1H),7.08(d,J=2.3Hz,1 H),7.03-6.95(m,1H),6.90(d,J=8.4Hz,1H),6.38-6.24(m,1H),6.22-6.10(m,1H),5.6 9-5.57(m,1H),5.16(p,J=7.0Hz,1H),3.84(s,3H),2.25(s,3H),1.51(d,J=6.9Hz,3H).

[0492] Example 97. Preparation of 1-(2-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one (Final Product 107)

[0493] Step 1: Dissolve (2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methanol (380.0 mg, 0.89 mmol) in dichloromethane (5 mL), cool to 0°C, add Dess-Martin reagent (1.1 g, 2.66 mmol), and stir at 0°C for 1 h. After the reaction was complete, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution at 0°C, and the mixture was extracted with dichloromethane / methanol (10 / 1 v / v, 20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using methanol / dichloromethane (10%) as eluent to give 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carbaldehyde (yellow oil, 250 mg, 66.1%). MS (ESI + )m / z=427.1[M+H] + .

[0494] Step 2: Under nitrogen protection, 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carbaldehyde (250.0 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0°C, and tert-butylsulfenamide (85.3 mg, 0.70 mmol) and tetraethyl titanate (267.5 mg, 1.17 mmol) were added in sequence, and stirred at room temperature overnight. After the reaction was complete, saturated sodium chloride solution (10 mL) was added to the reaction solution, and the mixture was filtered. The filter cake was washed with methanol (20 mL × 3). The filtrate was concentrated under reduced pressure, and the resulting residue was eluted with methanol / dichloromethane (10%) to obtain 2-methyl-N-((2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methylene)propane-2-sulfenamide (yellow oil, 150 mg, 48.3%). MS (ESI + )m / z=530.3[M+H] + .

[0495] Step 3: Under nitrogen protection, 2-methyl-N-((2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methylene)propane-2-sulfenamide (150.0 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL), cooled to -78 ° C, and (1,3-dioxane-2-ethyl)magnesium bromide (621.3 mg, 2.83 mmol) was added dropwise. The mixture was stirred at -78 ° C for 1 h. After the reaction was complete, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at -78°C, and the temperature was raised to room temperature. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by reverse phase C18 chromatography with acetonitrile / water (10%-50%-20 min) as the eluent to give N-(3-(1,3-dioxan-2-yl)-1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)propyl)-2-methylpropane-2-sulfenamide (white solid, 20 mg, 10.9%). MS (ESI) + )m / z=646.3[M+H] + .

[0496] Step 4: N-(3-(1,3-dioxan-2-yl)-1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)propyl)-2-methylpropane-2-sulfenamide (20.0 mg, 0.031 mmol) was dissolved in a mixture of trifluoroacetic acid and water (1 / 1 v / v, 1 mL) at 0°C and stirred for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to afford 5-(4-(3,4-dihydro-2H-pyrrol-5-yl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine as a yellow oil, 15 mg, crude. MS (ESI) + )m / z=466.3[M+H] + .

[0497] Step 5: Dissolve 5-(4-(3,4-dihydro-2H-pyrrol-5-yl)oxazol-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (15.0 mg, 0.032 mmol) in a mixture of trifluoroacetic acid and water (1 / 1 v / v, 1 mL), cool to -20°C, and add sodium triacetoxyborohydride (13.7 mg, 0.064 mmol). Return to room temperature and stir for 1 h. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(4-(pyrrolidin-2-yl)oxazol-2-yl)pyrimidin-4-amine (yellow oil, 15 mg, crude product). MS (ESI) + )m / z=468.3[M+H] + .

[0498] Step 6: Dissolve N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(4-(pyrrolidin-2-yl)oxazol-2-yl)pyrimidin-4-amine (15.0 mg, 0.032 mmol) in tetrahydrofuran (1 mL), add triethylamine (9.7 mg, 0.10 mmol), cool to 0°C, add acryloyl chloride (2.3 mg, 0.026 mmol) dropwise, and stir at room temperature for 15 min. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by high pressure preparative liquid chromatography (column type: XBridge BEH Shield RP18 Column, 19×250 mm, 5 μm; mobile phase: acetonitrile / water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: 35-56-10 min; wavelength: 254 / 220 nm) to give 1-(2-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one (4 mg, 25.1%).

[0499] White solid, MS (ESI + )m / z=522.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.76 (s, 0.5H), 10.60 (s, 0.5H), 8.94 (d, J = 3.8Hz, 1H), 8.73 (s, 1H), 8.37-8.10 (m, 2 H),7.78-7.47(m,3H),7.16-7.09(m,1H),7.00(dd,J=8.7,2.3Hz,1H),6.89(dd,J=8.7,2.0Hz,1H),6.72-6.61 (m,1H),6.24-6.12(m,1H),5.74-5.56(m,1H),5.10-5.47(m,1H),3.84(s,3H),3.82-3. 46(m,2H),2.34-2.22(m,4H),2.21-2.14(m,1H),2.13-2.05(m,1H),1.99-1.89(m,1H).

[0500] Example 98. Preparation of 1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-en-7-yl)prop-2-en-1-one (Final Product 108)

[0501] Step 1: Under nitrogen, 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (500 mg, 2.05 mmol) was added to a 40 mL bottle, cooled to -15°C, and BH3·THF (1 M, 5 mL) was slowly added dropwise. The temperature was raised to room temperature and stirred for 3 h. After the reaction was complete, methanol (10 mL) was slowly added dropwise until no bubbles were generated. The mixture was concentrated under reduced pressure, a small amount of ethyl acetate was added, and then a solution of hydrochloric acid in ethyl acetate was slowly added dropwise to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane / methanol (5 mL, 10 / 1). Sodium bicarbonate solution (5 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane / methanol (10 / 1 v / v, 5 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate (brown oil, 490 mg, crude product). MS (ESI + )m / z=231.0[M+H] + .

[0502] Step 2: 4-((3-Methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid (Intermediate A26, 815.0 mg, 2.17 mmol) was dissolved in N,N-dimethylformamide (5 mL). DIEA (420.9 mg, 3.26 mmol) and HATU (1.2 g, 3.26 mmol) were added sequentially and stirred at room temperature for 5 min. (3-Amino-1-Boc-3-piperidinyl)methanol (500.0 mg, 2.17 mmol) was then added and stirred at room temperature for 3 h. After the reaction was complete, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-15%) as the eluent to give tert-butyl 3-hydroxymethyl-3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)piperidine-1-carboxylate (yellow oil, 500 mg, 39.2%). MS (ESI + )m / z=588.3[M+H] +

[0503] Step 3: Under nitrogen, dissolve tert-butyl 3-hydroxymethyl-3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)piperidine-1-carboxylate (470.0 mg, 0.80 mmol) in dichloromethane (6 mL), cool to -78°C, and slowly add DAST (386.7 mg, 2.40 mmol) dropwise. Warm to room temperature and stir for 1 h. After the reaction was complete, aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by basic silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-8%) as the eluent to give tert-butyl 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate (white solid, 200 mg, 43.9%). MS (ESI + )m / z=570.4[M+H] + .

[0504] Step 4: Dissolve tert-butyl 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate (200.0 mg, 0.35 mmol) in dichloromethane (1 mL), cool to 0°C, add trifluoroacetic acid (1 mL), and stir at room temperature for 0.5 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure to afford 1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-yl)prop-2-en-1-one as a brown oil, 200 mg, crude. MS (ESI + )m / z=470.4[M+H] + .

[0505] Step 5: Dissolve 1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-en-7-yl)prop-2-en-1-one (180.0 mg, 0.38 mmol) in tetrahydrofuran (3 mL), add triethylamine (116.4 mg, 1.15 mmol), and then slowly add acrylic anhydride (24.2 mg, 0.19 mmol) dropwise and stir at room temperature for 0.5 h. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was separated and purified by high pressure preparative liquid chromatography (column type: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; mobile phase: acetonitrile / water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient: 28-58-7 min; wavelength: 254 / 220 nm) to give 1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-en-7-yl)prop-2-en-1-one (17 mg, 8.5%).

[0506] White solid, MS (ESI + )m / z=524.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.27(d,J=17.2Hz,1H),8.73(s,2H),8.17(s,1H),7.67 -7.47(m,3H),7.08(s,1H),7.02-6.74(m,3H),6.13-5.97(m,1H),5.73-5.47(m, 1H),4.31-4.15(m,3H),4.04-3.88(m,1H),3.84(s,3H),3.59-3.48(m,1H),3.09 (t,J=11.1Hz,1H),2.24(d,J=16.3Hz,3H),1.96-1.76(m,3H),1.67-1.51(m,1H).

[0507] Example 99. Preparation of N-(3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (Final Product 109)

[0508] Step 1: tert-Butyl (3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)carbamate

[0509] To a 25 mL reaction flask were added 5-((4-((5-iodopyrimidin-4-yl)amino)-2-methylphenyl)oxy)-1-methylbenzimidazole (Intermediate A2, 300 mg, 0.7 mmol), a 1,4-dioxane / water mixture (5 / 1, 3 mL), 3-((tert-butoxycarbonyl)amino)phenylboronic acid (233.3 mg, 1 mmol), Pd(PPh3)4 (75.8 mg, 0.07 mmol), and potassium carbonate (272 mg, 2.0 mmol). The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C and stirred for 1 h. The reaction was cooled to room temperature and quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using methanol / dichloromethane = 10%-15% as the eluent to obtain tert-butyl (3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)carbamate (yellow oil, 340 mg, 99.2%). MS (ESI + )m / z=523.4[M+H] + .

[0510] Steps 2 and 3: Preparation of N-(3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide

[0511] N-(3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide was prepared using tert-butyl (3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)carbamate as a raw material according to the synthesis methods of the second and third steps of Example 1.

[0512] White solid, MS (ESI + )m / z=477.2[M+H] + . 1H NMR (300MHz, DMSO-d6) δ10.31(s,1H),8.57(s,1H),8.44(s,1H),8.16(d,J=2.1Hz,2H),7.86-7.73(m,2H),7.57-7.33(m,4H), 7.20(dt,J=7.6,1.4Hz,1H),7.04(d,J=2.3Hz,1H),7.00-6.91(m,1H),6.78(d,J=8.7Hz, 1H),6.52-6.39(m,1H),6.34-6.21(m,1H),5.82-5.71(m,1H),3.83(s,3H),2.08(s,3H).

[0513] Example 100: N-(3-(2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (final product 112)

[0514] N-(3-(2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide was prepared using intermediate A11 and 3-((tert-butoxycarbonyl)amino)phenylboronic acid as starting materials according to the method for preparing final product 109.

[0515] White solid, MS (ESI+) m / z = 492.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.07(s,1H),7.77(s,1H),7.71-7.63( m,2H),7.60(s,1H),7.55-7.41(m,3H),7.33(t,J=7.9Hz,1H),7.04(d,J=2.3 Hz,1H),6.94(d,J=2.3Hz,1H),6.89(d,J=2.3Hz,1H),6.68(d,J=8.7Hz,1H), 6.47-6.31(m,1H),6.23(s,3H),5.73-5.64(m,1H),3.75(s,3H),2.09(s,3H).

[0516] Example 101. Preparation of N-(3-(4-amino-6-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (Final Product 110)

[0517] Under nitrogen, to a 25 mL single-necked flask were added 5-bromo-6-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-4-amine (Intermediate A10, 200 mg, 0.5 mmol), a 1,4-dioxane / water mixture (10 / 1, 5.5 mL), 3-(prop-2-enylamino)phenylboronic acid (134.7 mg, 0.7 mmol), Pd(dppf)Cl2 (34.4 mg, 0.05 mmol), and cesium carbonate (459.7 mg, 1.4 mmol). The mixture was heated to 90°C and stirred for 3 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high pressure preparative column chromatography (column type: XBridge Prep OBD C18 Column, 30 mm × 150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 60 mL / min; gradient: 24%-54% acetonitrile 7 min; wavelength: 254 / 220 nm) to obtain N-(3-(4-amino-6-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide.

[0518] White solid, MS (ESI + )m / z=492.2[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.14(s,1H),8.06(s,1H),7.89-7.79(m,1H),7.61-7.43(m,3H),7.37-7.26(m,2H),7.20 (s,1H),7.08-6.97(m,2H),6.96-6.89(m,1H),6.78-6.69(m,1H),6.52-6. 40(m,1H),6.31-6.22(m,1H),5.81-5.70(m,3H),3.82(s,3H),2.11(s,3H).

[0519] Example 102: Preparation of N-(3-(4-((2-methoxyethyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (Final Product 111)

[0520] N-(3-(4-((2-methoxyethyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide was prepared using intermediate A12 and 3-((tert-butoxycarbonyl)amino)phenylboronic acid as starting materials according to the method for preparing final product 110.

[0521] White solid, MS (ESI+) m / z = 550.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29 (s, 1H), 8.16 (d, J = 10.0Hz, 2H), 7.92-7.85 (m, 1H), 7.57-7.47(m,3H),7.33-7.25(m,2H),7.15(s,1H),7.04-6.96(m,2H),6.95-6.89( m,1H),6.73(d,J=8.4Hz,1H),6.51-6.40(m,1H),6.33-6.21(m,1H),5.82-5.71(m, 1H),5.50-5.41(m,1H),3.82(s,3H),3.51-3.36(m,4H),3.21(s,3H),2.11(s,3H).

[0522] Example 103. Preparation of 1-(6-(4-((3-methyl-4-(1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)prop-2-en-1-one (Final Product 113)

[0523] Step 1: tert-Butyl 6-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0524] Under nitrogen, 5-((4-((5-bromopyrimidin-4-yl)amino)-2-methylphenyl)oxy)-1-methylbenzimidazole (Intermediate A3, 340 mg, 0.8 mmol) was dissolved in 1,4-dioxane (10 mL). 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (378 mg, 2.0 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (RuphosPdG4, 74 mg, 0.09 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl gold(I) chloride (XPhosAuCl, 84 mg, 0.16 mmol) were added in sequence. The mixture was heated to 90°C and stirred for 1 h. The mixture was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) as the eluent to obtain tert-butyl 6-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (yellow solid, 320 mg, 68.7%). MS (ESI) + )m / z=528.1[M+H] + .

[0525] Second and third steps: 1-(6-(4-((3-methyl-4-(1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0526] Using tert-butyl 6-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a raw material, 1-(6-(4-((3-methyl-4-(1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)prop-2-en-1-one was prepared according to the synthesis method of the second and third steps of Example 1.

[0527] White solid, MS (ESI+) m / z = 482.2 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ8.18(d,J=16.5Hz,2H),8.05(s,1H),7.76(s,1H),7.62-7.45(m,3H),7.03(d,J=2.2Hz,1H),7.00-6.92(m,1H),6.82 (d,J=8.7Hz,1H),6.39-6.27(m,1H),6.18-6.05(m,1H),5.71-5.63(m, 1H),4.41(s,2H),4.13(s,2H),4.05(s,4H),3.83(s,3H),2.18(s,3H).

[0528] Example 104. Preparation of N-(7-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-7-azaspiro[3.5]nonan-2-yl)acrylamide (Final Product 114)

[0529] N-(7-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-7-azaspiro[3.5]nonan-2-yl)acrylamide was prepared using intermediate A3 and tert-butyl N-(7-azaspiro[3.5]nonan-2-ylcarbamate as raw materials and Pd-PEPPSI-IHept-Cl as catalyst according to the synthetic method of the final product 113.

[0530] White solid, MS (ESI+) m / z = 524.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ8.40-8.30(m,2H),8.20-7.99(m,3H),7.60-7.41(m,3H),6.98(s,1H),6.91(d,J=1.8Hz,1H),6.88(d, J=1.8Hz,1H),6.20-5.93(m,2H),5.58-5.42(m,1H),4.30-4.27(m,1H),3.76(s,3H),2.86-2.61(m,4H),2.22-2.08(m,5H),1.79-1.55(m,6H).

[0531] Example 105. Preparation of N-methyl-N-(2-(4-(3-methyl-4-(1-toluimidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethylacrylamide (Final Product 115)

[0532] Step 1: tert-Butyl methyl(2-((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl)carbamate

[0533] Under nitrogen, 5-(4-iodo-2-methylphenoxy)-1-methyl-1H-benzimidazole (Intermediate A16, 271.5 mg, 0.8 mmol) was dissolved in 1,4-dioxane (2 mL). Tert-butyl (2-((4-aminopyrimidin-5-yl)oxy)ethyl)(methyl)carbamate (Intermediate D1, 100 mg, 0.4 mmol), cuprous iodide (7.1 mg, 0.04 mmol), N,N-dimethylethylenediamine (3.3 mg, 0.04 mmol), and Cs2CO3 (531 mg, 1.6 mmol) were added sequentially. The mixture was heated to 90°C and stirred overnight. Ice water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using petroleum ether / ethyl acetate = 50% as the eluent to obtain tert-butyl methyl (2-((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl)carbamate (yellow oil, 100 mg, 53.2%). MS (ESI + )m / z=505.2[M+H] + .

[0534] Step 2: N-(3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)-5-(2-methylaminoethoxy)pyrimidin-4-amine

[0535] Under nitrogen, tert-butyl methyl (2-((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl)carbamate (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane (2 mL). A 4M hydrochloric acid solution in 1,4-dioxane (0.2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, sodium bicarbonate solution (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography using petroleum ether / ethyl acetate = 50% as the eluent to obtain N-(3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)-5-(2-methylaminoethoxy)pyrimidin-4-amine (yellow solid, 100 mg). MS (ESI) + )m / z=405.2[M+H]+ .

[0536] Step 3: N-methyl-N-(2-(4-(3-methyl-4-(1-toluene imidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethylacrylamide

[0537] N-(3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)-5-(2-methylaminoethoxy)pyrimidin-4-amine and acrylic anhydride were used as raw materials to prepare N-methyl-N-(2-(4-(3-methyl-4-(1-toluimidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethylacrylamide according to the synthesis method in the third step of Example 1.

[0538] White solid, MS (ESI+) m / z = 459.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.52-8.03(m,4H),7.75(d,J=2.8Hz,1H),7.71-7.62(m,1H),7.60-7.50(m,1H),7.14-6.78(m,4H ),6.23-6.10(m,1H),5.75-5.65(m,1H),4.37-4.26(m,2H),3.97-3.79(m,5H),3.21-2.97(m,3H),2.21(d,J=2.8Hz,3H).

[0539] Examples 106-107. Preparation of Final Product 117 and Final Product 118

[0540] The preparation method of final product 115 was adopted, and intermediate A16 and intermediates D2-D3 were used as raw materials to prepare final products 117 and 118, as shown in Table 9.

[0541] Table 9 Final products 117 and 118

[0542] Example 108. Preparation of 1-(2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one (Final Product 116)

[0543] Step 1: tert-Butyl 2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate

[0544] 4-((3-Methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-ol (Intermediate A15, 160 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (5 mL), and tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (93.0 mg, 0.75 mmol) and cesium carbonate (451.6 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were backwashed three times with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography (ethyl acetate / petroleum ether = 50%) to give tert-butyl 2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (yellow oily liquid, 90 mg, 36.8%).

[0545] Steps 2 and 3: Preparation of 1-(2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one

[0546] Using tert-butyl 2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate as a raw material, 1-(2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one was prepared according to the synthetic methods of the second and third steps of Example 1.

[0547] White solid, MS (ESI+) m / z = 493.1 [M+H] + . 1H NMR(300MHz,CD3OD)δ8.22(s,1H),8.10(s,1H),7.97(s,1H),7.76-7.71(m,1H), 7.69-7.63(m,1H),7.61-7.46(m,1H),7.13-7.05(m,2H),6.88(d,J=8.7Hz,1H), 6.75-6.63(m,1H),6.42-6.32(m,1H),5.86-5.75(m,1H),4.81-4.69(m,1H),4.3 3-4.11(m,2H),3.91(s,3H),3.84-3.60(m,2H),2.28(s,3H),2.21-2.00(m,5H).

[0548] Example 109. Preparation of 1-(4-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Final Product 120)

[0549] 1-(4-((4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)piperidin-1-yl)prop-2-en-1-one was prepared using intermediate A15 and tert-butyl 4-iodopiperidine-1-carboxylate as raw materials according to the preparation method of the final product 116.

[0550] White solid, MS (ESI+) m / z = 485.4 [M+H] + . 1 H NMR (300MHz, CDCl3) δ8.42 (s, 1H), 8.01-7.90 (m, 2H), 7.55 (d, J = 2.7Hz, 1H), 7.52- 7.43(m,2H),7.40-7.26(m,1H),7.14-7.04(m,2H),6.96-6.87(m,1H),6.71-6.58(m ,1H),6.41-6.31(m,1H),5.81-5.71(m,1H),4.77-4.64(m,1H),4.25-4.06(m,1H), 3.88(s,4H),3.70-3.52(m,2H),2.33(s,3H),2.13-2.10(m,2H),1.99-1.87(m,2H).

[0551] Example 110. Preparation of N-(1-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-3-(1-methylpyrrolidin-2-yl)propynamide (Final Product 164)

[0552] Step 1: tert-Butyl 2-(3-((1-((4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)amino)-3-oxopropyl-1-yn-1-yl)pyrrolidine-1-carboxylate was prepared from 5-((1-aminocyclopropyl)ethynyl)-N-(3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine and 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)propiolic acid (Intermediate C4) as starting materials according to the method of Step 3 of the synthesis of final product 58. MS (ESI) + )m / z=632.3[M+H] + .

[0553] Step 2: Starting from tert-butyl 2-(3-((1-((4-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)amino)-3-oxopropyl-1-yn-1-yl)pyrrolidine-1-carboxylate, N-(1-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)amino)-3-oxopropyl-1-yn-1-yl)pyrrolidine-1-carboxylate was prepared according to the procedure for the second step of the synthesis of the final product 1 (yellow solid, 150 mg, crude). MS (ESI) + )m / z=532.3[M+H] + .

[0554] Step 3: Under nitrogen, dissolve N-(1-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-3-(pyrrolidin-2-yl)propynamide (140.0 mg, 0.26 mmol) in methanol (3 mL). Cool to 0°C, slowly add formaldehyde aqueous solution (11.9 mg, 0.40 mmol) dropwise, and then add sodium cyanoborohydride (82.7 mg, 1.32 mmol). Warm to room temperature and stir for 1 h. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by high pressure preparative liquid chromatography (column type: XBridge Prep OBD C18 Column, 19×250 mm, 5 μm; mobile phase: acetonitrile / water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: 34-64-7 min; wavelength: 254 / 220 nm) to obtain N-(1-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-3-(1-methylpyrrolidin-2-yl)propynamide.

[0555] White solid, MS (ESI + )m / z=546.3[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.48(s,1H),8.55(s,1H),8.45(s,1H),8.33(s,1H),8.17(s,1H),7.69(d ,J=2.4Hz,1H),7.57(dd,J=8.7,2.7Hz,2H),7.08(d,J=2.3Hz,1H),6.99(dd,J=8.7,2.3Hz,1H),6 .85(d,J=8.7Hz,1H),3.84(s,3H),3.32-3.26(m,1H),2.75-2.64(m,1H),2.40-2.29(m,1H),2.28 (s,3H),2.23(s,3H),2.17-1.99(m,1H),1.86-1.63(m,3H),1.45-1.31(m,2H),1.23-1.14(m,2H).

[0556] Example 111. Preparation of N-methyl-N-((2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide (Final Product 167)

[0557] Step 1: Dissolve 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carbaldehyde (91.0 mg, 0.21 mmol) in methanol (10 mL). Add methylamine (13.3 mg, 0.43 mmol) and stir at room temperature for 0.5 h. Then add NaBH3CN (67.0 mg, 1.07 mmol) and stir at room temperature for 0.5 h. After the reaction was complete, dichloromethane (30 mL) was added to the reaction solution, and the mixture was washed with water (30 mL × 3). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(4-((methylamino)methyl)oxazol-2-yl)pyrimidin-4-amine (yellow solid, 57 mg, 60.5%). MS (ESI + )m / z=442.0[M+H] + .

[0558] Step 2: Using N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(4-((methylamino)methyl)oxazol-2-yl)pyrimidin-4-amine as starting material, prepare N-methyl-N-((2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide (2 mg, 3.1%) according to the method of Step 3 of Example 1.

[0559] White solid, MS (ESI + )m / z=496.2[M+H] + . 1H NMR (300MHz, DMSO-d6) δ10.96 (s, 0.5H), 10.65 (s, 0.5H), 8.95 (d, J = 3.5Hz, 1 H),8.73(s,1H),8.35(s,0.5H),8.28(s,0.5H),8.17(s,1H),7.70-7.50(m,3 H),7.18-6.77(m,4H),6.28-6.17(m,1H),5.79-5.68(m,1H),4.72(s,1H),4. 64(s,1H),3.83(s,3H),3.13(s,1.5H),2.94(s,1.5H),2.24(d,J=2.8Hz,3H).

[0560] Example 112 Preparation of N-((2-(4-amino-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide (Final Product 168)

[0561] Step 1, step 2, step 3: Using 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid methyl ester (intermediate E6) as starting material, 5-(4-(aminomethyl)oxazol-2-yl)-N-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid methyl ester (intermediate E6) was prepared according to the first, second, and third steps of the final product 81. 4 -(4-methoxybenzyl)-N 6 -(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (yellow solid, 95 mg, 77.2%). MS (ESI + )m / z=564.3[M+H] + .

[0562] Step 4: 5-(4-(aminomethyl)oxazol-2-yl)-N 4 -(4-methoxybenzyl)-N 6 -(3-Methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (95.0 mg, 0.17 mmol) was dissolved in a mixture of trifluoroacetic acid and water (9 / 1 v / v, 3 mL) and stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure, methanol / dichloromethane (1 / 10 v / v, 20 mL) was added, and the pH was adjusted to 7 with sodium bicarbonate. The organic phase was separated and washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5-(4-(aminomethyl)oxazol-2-yl)-N4 -(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (yellow solid, 62 mg, 83.0%). MS (ESI + )m / z=443.3[M+H] + .

[0563] Step 5: 5-(4-(aminomethyl)oxazol-2-yl)-N 4 -(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine was used as the starting material and N-((2-(4-amino-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide was prepared according to the fourth step method of final product 81.

[0564] White solid, MS (ESI + )m / z=497.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.92(s,1H),8.65(t,J=5.8Hz,1H),8.16(s,1H),8.10(s, 1H),8.05(s,1H),7.62-7.52(m,3H),7.40(s,2H),7.05(d,J=2.2Hz,1H),6.97(dd, J=8.7,2.3Hz,1H),6.87-6.82(m,1H),6.30(dd,J=17.1,9.9Hz,1H),6.19-6.12(m, 1H), 5.63 (dd, J=10.0, 2.4Hz, 1H), 4.40 (d, J=5.4Hz, 2H), 3.84 (s, 3H), 2.21 (s, 3H).

[0565] Example 113. 1-(2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.4]non-1-en-7-yl)prop-2-en-1-one (Final Product 169)

[0566] 1-(4-((4-((3-Methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid was used as the starting material to prepare 1-(4-((4-((3-Methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)piperidin-1-yl)prop-2-en-1-one according to the method for synthesizing final product 108.

[0567] White solid, MS (ESI + )m / z=510.2[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ11.21(s,1H),8.73(d,J=4.9Hz,2H),8.23-8.16(m,1H),7.60-7.49(m,3H),7.08(d,J=2.1Hz,1H),7.01-6.93(m,1 H),6.90-6.82(m,1H),6.76-6.47(m,1H),6.22-6.10(m,1H),5.76-5.62(m,1H),4.52-4.45(m,2H),3.91-3.52(m,7H),2.32-2.13(m,5H).

[0568] Example 114. Preparation of 1-(2-(4-amino-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-en-7-yl)prop-2-en-1-one (Final Product 170)

[0569] Step 1: Using intermediate A25 and (3-amino-1-Boc-3-piperidinyl)methanol as starting materials, tert-butyl 3-(4-chloro-6-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)-3-(hydroxymethyl)piperidine-1-carboxylate (pale yellow solid, 446 mg, 42.0%) was prepared according to the second step method for synthesizing final product 108. MS (ESI) + )m / z=622.4[M+H] + .

[0570] Step 2: 3-(Hydroxymethyl)-3-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)piperidine-1-carboxylate (light yellow oil, 370 mg, 71.4%) was prepared according to the procedure for the second step of the synthetic intermediate E6 using tert-butyl 3-(4-chloro-6-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)-3-(hydroxymethyl)piperidine-1-carboxylate and p-methoxybenzylamine as starting materials. MS (ESI) + )m / z=723.5[M+H] + .

[0571] Step 3: Starting from tert-butyl 3-(hydroxymethyl)-3-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-)((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxamido)piperidine-1-carboxylate, tert-butyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate (light yellow oil, 180 mg, 49.9%) was prepared according to the method of Step 3 of the synthesis of final product 108. MS (ESI) + )m / z=705.5[M+H] + .

[0572] Step 4: In a 40 mL sample vial, tert-butyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate (180 mg, 0.26 mmol) was dissolved in a mixture of trifluoroacetic acid and water (4.4 mL, 1 / 10 v / v), heated to 80 °C and stirred for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give tert-butyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate (light yellow oil, 250 mg, crude product). MS (ESI) + )m / z=485.3[M+H] + .

[0573] Step 5: Using tert-butyl 2-(4-((4-methoxybenzyl)amino)-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-carboxylate as raw material, 1-(2-(4-amino-6-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)-3-oxa-1,7-diazaspiro[4.5]dec-1-ene-7-yl)prop-2-en-1-one was prepared according to the method of the third step of synthesizing the final product 1.

[0574] White solid, MS (ESI + )m / z=539.4[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ11.48(d,J=47.1Hz,1H),8.16(s,1H),8.05(s,1H),7.55(d,J=8.8Hz ,2H),7.48-7.37(m,1H),7.37-7.09(m,2H),7.04(s,1H),7.01-6.87(m,1H),6.87-6.79(m,2H ),6.05(t,J=15.6Hz,1H),5.70-5.48(m,1H),4.27-4.04(m,3H),3.84(s,4H),3.53(d,J=13. 2Hz,1H),3.14(t,J=9.0Hz,1H),2.20(d,J=9.0Hz,3H),1.94-1.71(m,3H),1.66-1.50(m,1H).

[0575] Comparative Compound A

[0576] Comparative compound A was prepared using 3,4-dichloro-2-fluoroaniline and 4-chloro-5-iodopyrimidine as starting materials according to the method of final product 1.

[0577] MS (ESI + )m / z=403.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.26(s,1H),8.66(s,1H),8.52(s,1H),8.41(s,1H),7.75- 7.66(m,1H),7.61-7.53(m,1H),1.96(s,3H),1.43-1.31(m,2H),1.19-1.09(m,2H). 19F NMR(282MHz,DMSO-d6)δ-115.570,-116.095.

[0578] Experimental Example 1 Cell proliferation inhibition experiment

[0579] CellTiter-Glo TM The live cell detection kit uses luciferase as a detector, and luciferase requires the participation of ATP in the luminescence process. Add CellTiter-Glo to the cell culture medium. TM The light signal is proportional to the amount of ATP in the system, which in turn is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to measure ATP content, cell proliferation can be monitored.

[0580] In this experiment, the Celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the above-prepared compounds in the tumor cell lines HER2775-776insYVMA Ba / F3 cell line and SK-BR-3 cell line, and the 50% inhibitory concentration IC was calculated. 50 .

[0581] 1. Experimental Design

[0582] Compounds were tested on selected cells and vehicle controls were set up for a total of 9 concentrations, with 2 replicates for each concentration.

[0583] 2. Reagents and Consumables

[0584] 3. Experimental Procedure

[0585] 3.1 Cell culture

[0586] a) All cells were cultured according to ATCC recommended methods. Cells were harvested during the logarithmic growth phase. Cell viability was measured to ensure that the cell viability was above 90%.

[0587] b) Cell culture medium: RPMI1640, 10% FBS, 1% P / S. Adjust the cell concentration and add 95 μL or 90 μL of cell suspension to a 96-well plate.

[0588] c) Cell culture environment: culture at 37°C, 5% CO2, and 95% humidity.

[0589] 3.2 Drug dilution

[0590] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0591] b) Drug Storage: DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.

[0592] c) Prepare 20X or 10X drug solution: Add 2 μL of drug stock solution to 98 μL or 198 μL of cell culture medium.

[0593] 3.3 Dosing

[0594] a) All drugs were diluted 3-fold starting from 1 μM, with 9 concentration steps or 4-fold dilutions, with 8 concentration steps.

[0595] b) Prepare positive control drug and DMSO blank control.

[0596] c) Add 5 μL of 20X drug solution or 10 μL of 10X drug to each well of a 96-well plate seeded with cells, and set up two replicate wells for each drug concentration.

[0597] d) The cells in the drug-added 96-well plate were cultured at 37° C., 5% CO 2 , and 95% humidity for 72 hours before CTG analysis.

[0598] 3.4 Endpoint plate reading

[0599] a) Thaw CTG reagent, add 50 μL of CTG solution to each well, and shake well.

[0600] b) Place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal.

[0601] c) Read the fluorescence value using a microplate reader.

[0602] 4. Data Processing

[0603] GraphPad Prism 7.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 Inhibition rate (Inh%) = 100-(RLU 化合物 -RLU 空白 ) / (RLU 对照 -RLU 空白 )*100%.

[0604] 5. Experimental Results

[0605] The proliferation inhibitory activity of the compounds against HER2 775_776insYVMA Ba / F3 cell line and SK-BR-3 cell line is shown in Table 10.

[0606] Table 10. Antiproliferative activity of compounds against HER2 775_776insYVMA Ba / F3 cell line and SK-BR-3 cell line (IC 50 ,nM)

[0607] As can be seen from the table, the compounds of the present invention have good anti-proliferation activity against HER2 775-776insYVMA Ba / F3 cell line (expressing HER2 exon 20 insertion mutation) and SK-BR-3 cell line (HER2 overexpression), and the inhibition IC 50 reaching nanomolar concentrations.

[0608] Example 2: A431 phosphorylation experiment

[0609] Cell culture

[0610] a) All cells were cultured according to ATCC recommended methods. Cells were harvested during the logarithmic growth phase. Cell viability was measured to ensure that the cell viability was above 90%.

[0611] b) Cell culture medium: DMEM, 10% FBS, 1% Glutamax, and 1% P / S. Adjust the cell concentration and add 40 μL of the cell suspension to each well of a 384-well plate. Centrifuge at 1000 rpm for 30 seconds and incubate for 4 hours.

[0612] c) Remove the culture medium and add 25 μL of HBSS to the 384-well plate and leave overnight.

[0613] 3.2 Drug dilution

[0614] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0615] b) Drug Storage: DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.

[0616] 3.3 Dosing

[0617] a) All drugs were diluted 3-fold starting from 10 mM concentration, with 10 concentration steps.

[0618] b) The cells in the drug-added 384-well plate were cultured for 30 minutes at 37° C., 5% CO 2 , and 95% humidity.

[0619] 3.4 Detection

[0620] a) Add EGF as an activator and stimulate for 15 minutes.

[0621] b) Cell lysates were prepared and assayed according to the manufacturer's protocol.

[0622] c) AlphaScreen is read by Envision.

[0623] 4. Data Processing

[0624] GraphPad Prism 8.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 Inhibition rate (Inh%) = 100-(Signal 化合物 -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )*100%.

[0625] Signal Ave_PC : Average signal of positive control on the whole plate

[0626] Signal Ave_VC : Average signal of negative control across the entire plate

[0627] Table 11. Compounds inhibit EGFR phosphorylation of pEGFR in A431 cells (IC 50 nM)

[0628] As can be seen from the table, the compounds of the present invention inhibit the EGFR phosphorylation of A431 cell line IC 50 The value is >1 μM, indicating that the compound of the present invention has weak inhibition on wild-type EGFR and has good selectivity for wild-type EGFR.

[0629] Example 3: P-gp substrate evaluation experiment

[0630] 1. Experimental Design

[0631] Cell culture

[0632] 1) Use high-glucose DMEM medium containing L-glutamine, supplemented with 10% fetal bovine serum, 0.1 mg / mL streptomycin, and 0.6 μg / mL penicillin.

[0633] 2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks in an incubator set at 37°C, 5% CO2, and 95% relative humidity. Cells were seeded in Transwell plates when they reached 70-90% confluence.

[0634] 3) Before cell seeding, add 50 μL of cell culture medium to each well of the upper Transwell chamber and 25 mL of cell culture medium to the lower culture plate. Incubate the culture plate in a 37°C, 5% CO2 incubator for 1 hour before seeding the cells.

[0635] 4) Gently rinse the cells with 5 mL of PBS. Discard the PBS and add 1.5 mL of trypsin containing EDTA. Incubate at 37°C for 5 to 10 minutes until the cells are completely detached. Add serum-containing medium to terminate the digestion.

[0636] 5) Transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120 × g for 10 minutes.

[0637] 6) Resuspend the cells in culture medium to a final concentration of 1.56 × 10 6 cells / mL.

[0638] MDCKII-MDR1 cell inoculation

[0639] 1) Add 50 μL of cell suspension to each well of a 96-well Transwell culture plate, and the final seeding density is

[0640] 1.45×10 5 cells / cm 2 .

[0641] 2) Start changing the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

[0642] Assessment of cell monolayer integrity

[0643] 1) After 4-8 days of culture, MDCKII-MDR1 and MDCKII should be fully confluent and differentiated. At this point, they can be used for penetration assays.

[0644] 2) The resistance of the monolayer membrane was measured using a resistance meter (Millipore, USA), and the resistance of each pore was recorded.

[0645] 3) After the assay is completed, place the Transwell culture plate back into the incubator.

[0646] 4) Calculation of resistance value:

[0647] Measure the resistance value (ohms) x film area (cm 2 )=TEER value (ohm·cm 2 )

[0648] If the TEER value is less than 42 ohms·cm 2 , then the hole cannot be used for penetration test.

[0649] Drug penetration test

[0650] 1) Remove the MDCKII-MDR1 Transwell plate from the incubator. Rinse the cell monolayer twice with HBSS (10 mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes.

[0651] 2) Determine the transport rate of the compound from the apical to the basolateral side. Add 125 μL of test drug or control drug in HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical) and 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the lower chamber (basolateral).

[0652] 3) Determine the transport rate of the compound from the basolateral to the apical side. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical side), and add 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control drug to each well of the lower chamber (basolateral side).

[0653] 4) Combine the upper and lower transfer devices and incubate at 37°C for 2 hours.

[0654] 5) After incubation, sample 50 μL from each well of the upper and lower chambers of the Transwell plate and transfer to new sample tubes. Add 4 volumes of acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 200 nM diclofenac, 100 nM tolbutamide) to each tube. Vortex for 5 minutes and centrifuge at 3,220 g for 15 minutes. Aspirate 100 μL of the supernatant, dilute with an equal volume of water, and perform LC-MS / MS analysis. All samples were prepared in triplicate.

[0655] 6) After 2 hours of incubation, the integrity of the cell monolayer membrane was assessed by fluorescein leakage. The fluorescein stock solution was diluted to a final concentration of 100 μM in HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescein solution was added to each well of the upper Transwell insert, and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from each well and transferred to a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0656] 2. Data Processing

[0657] The data were calculated using Excel. The apparent permeability coefficient (P app, unit: cm / s) is calculated using the following formula:

[0658] The membrane area in the formula is the Transwell-96 well plate membrane area (0.143 cm 2 ); incubation time is in seconds (s). The efflux rate is calculated using the following formula:

[0659] Table 12. Efflux rates of test compounds

[0660] Example 4: Cassette pharmacokinetic test of compounds in mice

[0661] Experimental purpose: Using ICR mice as test subjects, the LC / MS / MS method was used to determine the drug concentration of the compound in plasma at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after oral gavage (PO) administration. The pharmacokinetic behavior of the compound of the present invention in mice was studied and its pharmacokinetic characteristics were evaluated.

[0662] Drug Preparation: The compounds were prepared into clear solutions using 10% DMSO + 10% Solutol HS 15 + 5% Cremophor EL + 20% PEG400 + 55% (20% Captisol aqueous solution) as the solvent for PO administration. The administration method was cassette dosing. The compound dosage was 10 mg / kg. The pharmacokinetic parameters are shown in Table 13.

[0663] Table 13. Pharmacokinetic test results of cassette in mice

[0664] As can be seen from Table 13, the compounds of the present invention have good exposure.

[0665] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A nitrogen-containing heteroaromatic ring compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof: in, In Formula I, M is N or CR 3 ; X is N or CR 4 ; A is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylthio, 3-12 membered cycloalkylthio, 3-12 membered heterocyclylthio, 3-12 membered cycloalkyl-C 1-6 Alkylene-mercapto or 3-12 membered heterocyclic-C 1-6 Alkylene-mercapto, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylthio, 3-12 membered cycloalkylthio, 3-12 membered heterocyclylthio, 3-12 membered cycloalkyl-C 1-6 Alkylene-mercapto and 3-12 membered heterocyclyl-C 1-6 Alkylene-mercapto is optionally substituted with one or more R′; Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted by one or more R′; Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more R′; Z is C(=O) or S(O)2; L1 is NR 8 , O, CR 5 R 6 , S, S(O) or S(O)2; L2 is a chemical bond, O, NR 8 , CR 5 R 6 , C(=O), S, S(O) or S(O)2; E is a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are optionally substituted by one or more R e replace; G is Said optionally substituted with one or more R′; -- is none or a single key; Ring B is a 5-6 membered heteroaryl, a 5-7 membered heterocyclyl or a 5-7 membered cycloalkyl; X 1 is a chemical bond, N, CH, CH2, O, S, S(O) or S(O)2; X 2 is N, CH, CH2, O, S, S(O) or S(O)2; X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 , X 2 and X 3 Not all are N; X 5 is a chemical bond, N, CH, CH2, O, S, S(O) or S(O)2; X 6 For N, O, S, C(=O), S(O), S(O)2, N(=O), N(O)2, N + -O - Some CH; R 1 For halomethyl, C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide or C 4-6 Cycloalkenyl, the C 2-4 Alkenyl, C 2-4 Alkynyl, propylene oxide and C 4-6 The cycloalkenyl group is optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, 6-12 membered aryl, C 1-3 Alkoxy-C 1-3 Alkyl- or NR a R b Substitute, the C 1-4 Alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl and C 1-3 Alkoxy-C 1-3 Alkyl - optionally substituted with one or more R'; R 2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl or 3-12 membered heterocyclic group, the hydroxyl, amino, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with one or more R'; R 3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted by one or more R′; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or di(C 1-6 alkyl)amino group, wherein the amino group, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered ring Alkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted by one or more R′; R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclyl-C 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, 3-12 membered cycloalkyl-C 1-6 Alkyl- and 3-12 membered heterocyclyl-C 1-6 Alkyl-optionally substituted with one or more R′; or R 5 With R 6 Together with the attached C atom, it forms a 3-12 membered cycloalkyl or a 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and the 3-12 membered heterocyclyl are optionally substituted by one or more R′; R 7 For hydrogen atoms, C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 haloalkyl, 5-12 membered heteroaryl or 6-12 membered aryl, the C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Haloalkyl, 5-12 membered heteroaryl and 6-12 membered aryl are optionally substituted with one or more R'; R 8 For hydrogen atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 Alkyl- or hydroxyl C 1-6 alkyl; R a and R b are independently a hydrogen atom, C 1-4 Alkyl, C 1-4 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic-C 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- or deuterated C 1-4 Alkyl, the C 1-4 Alkyl, C 1-4 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-4 Alkyl-, 3-12 membered heterocyclic-C 1-4 Alkyl-, C 1-4 Alkoxy-C 1-4 Alkyl- and deuterated C 1-4 The alkyl group is optionally substituted with one or more R′; or R a With R b Together with the N atom to which it is attached, it forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally substituted by one or more R′; R c and R d are independently a hydrogen atom, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 Alkyl- or 3-12 membered heterocyclyl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 Alkyl- and 3-12 membered heterocyclyl-C 1-6 Alkyl - optionally substituted with one or more R'; R e For deuterium atoms, halogens, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, OR e1 , SR e1 , SOR e1 、SO2R e1 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 NR e1 R e2 NR e1 C(=O)R e2 、OC(=O)R e1 ,SONR e1 、SO2NR e1 、NHS(O)2R e1 、NHS(O)R e1 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、-(O)(OR e1 )2 or P(O)(R e1 ) 2, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Heteroalkenyl, C 2-6 heteroalkynyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, C 1-6 Haloalkyl and C 1-6 The haloalkoxy group is optionally substituted with one or more R′; R e1 and R e2 are independently a hydrogen atom, a deuterium atom, a C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group or R e1 and R e2 Together with the attached N atom, it forms a 3-12 membered heterocyclic group; R' is independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-4 Alkyl, deuterated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkoxy or oxo (=O).

2. The nitrogen-containing heteroaromatic ring compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In formula I, M is N or CR 3 ; R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted by one or more R'; R c and R d Each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group, optionally substituted by one or more R′; R′ is a deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or oxo (═O); Preferably, in formula I, M is N or CR 3 ; R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or NR c C(=O)R d , the hydroxyl group, amino group, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and NR c C(=O)R d Optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo; More preferably, in Formula I, M is N or CR 3 ; R 3 It is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-propoxy group, a piperazin-1-yl-propoxy group, a pyrrolidin-1-yl-ethoxy group, a pyrrolidin-1-yl-propoxy group, a tetrahydrofuran-3-oxy group, a methylthio group, a methylamino group, an ethylamino group, an acetamido group, a propionamido group, a methoxyethyl group, a methoxyethylamino group or a methoxyethoxy group.

3. The nitrogen-containing heteroaromatic ring compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, wherein: In formula I, X is N or CR 4 ; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R′; R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy; Preferably, in formula I, X is N or CR 4 ; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R′; R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy; Preferably, in formula I: A is C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy or 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, the C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy and 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy is optionally substituted with one or more R′; Preferably, A is ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy or tetrahydropyrrolylmethyleneoxy, the ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidine 4-(4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, 4-(4-oxo)-1-ol, More preferably, A is selected from the following groups: Optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy.

4. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 3, wherein: In Formula I: Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino or 3-12 membered cycloalkyl-C 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino and 3-12 membered cycloalkyl-C 1-6 Alkyl - optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy; or R 5 and R 6 Together with the C atom to which it is attached, it forms a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and the 3-12 membered heterocyclyl are optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; Preferably, in Formula I, Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 5 and R 6 each independently represents a hydrogen atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl group, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl groups are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups.

5. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 4, wherein: In Formula I: Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Preferably, in Formula I, Y 2 is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or a NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Preferably, in formula I: Z is C(═O) or S(O)2; Preferably, in Formula I, L1 is NR 8 or O; R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxyl group. 1-6 Ethyl; Preferably, in Formula I, L1 is NR 8 ; R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group; Preferably, in Formula I, L2 is a chemical bond, O, CH or C(═O).

6. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 5, wherein: In Formula I: E is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by one or more R e replace; R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; Preferably, in Formula I, E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted by one or more R e replace; R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; Preferably, in formula I: G is Optionally, one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclo substituted with propyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; -- is none or a single key; Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2; X 2 is N, CH, CH2, O, S, S(O) or S(O)2; X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 , X 2 and X 3 Not all are N; X 5 is a chemical bond, N, CH, CH2, O or S; X 6 is N, O, S or CH; Preferably, in formula I, G is selected from the following groups: optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; More preferably, in formula I, G is selected from the following groups:

7. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 6, wherein: In Formula I: R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl and cyclohexenyl group are optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, oxetyl, oxetyl, deuterium atom, phenyl, pyridyl or NR a R b Substituted, the methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl and pyridinyl are optionally substituted by one or more R'; R a and R b each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an acridinylmethyl group or an acridinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the adamantyl group, the methoxyethyl group, the cyclopropylmethyl group, the cyclobutylmethyl group, the cyclopropylethyl group, the cyclobutylethyl group, the acridinylmethyl group and the acridinylethyl group are optionally substituted by one or more R′; or R a With R b and the N atom to which it is attached form an acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexanyl radical, said acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptyl and 2-azabicyclo[3.1.0]hexanyl radical being optionally substituted with one or more R′; R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo (═O) Preferably, in Formula I, R 1 Selected from the following groups:

8. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 7, wherein: In Formula I: R 2 For hydrogen atoms, deuterium atoms, F, Cl, cyano groups, amino groups, C 1-4 Alkyl or 3-6 membered cycloalkyl; Preferably, in Formula I, R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group; Preferably, in Formula I, M is N or CR 3 ; R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, C(=O)NR c NR c C(=O)R d or NR c C(=O)NR d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and di(C 1-6 Alkyl)amino is optionally substituted by one or more R'; R c and R d Each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group, optionally substituted by one or more R′; X is N or CR 4 ; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the isopropyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R′; A is C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy or 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, the C 2-4 Alkenyl, C 2-4 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C 1-6 Alkylene-oxy and 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy is optionally substituted with one or more R′; Y 1 For chemical bonds, CR 5 R 6 , 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl and 3-12 membered heterocyclyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 5 and R 6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C 1-6 Alkyl, halogenated C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino or 3-12 membered cycloalkyl-C 1-6 Alkyl-, the hydroxyl, amino, C 1-6 Alkyl, halogen Generation C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkylamino and 3-12 membered cycloalkyl-C 1-6 Alkyl - optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy; Y 2 is a chemical bond, a 3-12 membered heterocyclic group or NR 7 , the 3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Z is C(=O) or S(O)2; L1 is NR 8 or O; R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an acetonitrile group or a hydroxyl group. 1-6 Ethyl; L2 is a chemical bond, O, CH or C(=O); E is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by one or more R e replace; R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; G is optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; -- is none or a single key; Ring B is pyrrole, imidazole, pyrazole, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; X 1 is a chemical bond, N, CH, CH2, S, O, S(O) or S(O)2; X 2 is N, CH, CH2, O, S, S(O) or S(O)2; X 3 and X 4 are each independently N or C, and X 3 and X 4 Not N, X at the same time 1 , X 2 and X 3 Not all are N; X 5 is a chemical bond, N, CH, CH2, O or S; X 6 is N, O, S or CH; or R 1 is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl and cyclohexenyl group are optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, oxetyl, oxetyl, deuterium atom, phenyl, pyridyl or NR a R b Substituted, the methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl and pyridinyl are optionally substituted by one or more R'; R a and R b each independently represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an acridinylmethyl group or an acridinylethyl group, wherein the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the adamantyl group, the methoxyethyl group, the cyclopropylmethyl group, the cyclobutylmethyl group, the cyclopropylethyl group, the cyclobutylethyl group, the acridinylmethyl group and the acridinylethyl group are optionally substituted by one or more R′; or R a With R b and the N atom to which it is attached form an acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl or 2-azabicyclo[3.1.0]hexanyl radical, said acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptyl and 2-azabicyclo[3.1.0]hexanyl radical being optionally substituted with one or more R′; R′ is a deuterium atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, vinyl, ethynyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo (═O); R 2 For hydrogen atoms, deuterium atoms, F, Cl, cyano groups, amino groups, C 1-4 Alkyl or 3-6 membered cycloalkyl; Preferably, in Formula I: M is N or CR 3 ; R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino or NR c C(=O)R d , the hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-12 membered heterocyclyloxy, R c R d NC 1-6 Alkylene-oxy, 3-12 membered heterocyclyl-C 1-6 Alkylene-oxy, C 1-6 Alkylmercapto, C 1-6 Alkylamino and NR c C(=O)R d Optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo; X is N or CR 4 ; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R′; R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy; A is ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy or tetrahydropyrrolylmethyleneoxy, and the ethynyl, propynyl, 2,6-diazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane , phenyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 3-oxa-1,7-diazaspiro[4.5]non-1-ene, 4,5-dihydrooxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrrolyloxy, acridinyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy and tetrahydropyrrolylmethyleneoxy are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy; Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 5 and R 6 each independently represents a hydrogen atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxacyclopentyl or oxacyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; Y 2 is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or a NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Z is C(=O) or S(O)2; L1 is NR 8 ; R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group; L2 is a chemical bond, O, CH or C(=O); E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, wherein the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted by one or more R e replace; R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; G is selected from the following groups: optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, deuterated methyl, ethyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; R 1 Selected from the following groups: R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group; More preferably, in Formula I: M is N or CR 3 ; R 3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a hydroxyethoxy group, an N',N'-dimethylaminoethoxy group, an N'-methylaminoethoxy group, a morpholinyl-ethoxy group, a hydroxypropoxy group, an N',N'-dimethylaminopropoxy group, an N'-methylaminopropoxy group, a morpholinyl-propoxy group, a piperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-ethoxy group, a 4-methylpiperazin-1-yl-propoxy group, a piperazin-1-yl-propoxy group, a pyrrolidin-1-yl-ethoxy group, a pyrrolidin-1-yl-propoxy group, a tetrahydrofuran-3-oxy group, a methylthio group, a methylamino group, an ethylamino group, an acetamido group, a propionamido group, a methoxyethyl group, a methoxyethylamino group or a methoxyethoxy group; X is N or CR 4 ; R 4 is a hydrogen atom, a halogen, a cyano group, an amino group, a methyl group, an ethyl group, a cyclopropyl group, a methoxy group or a cyclopropyloxy group, wherein the amino group, the methyl group, the ethyl group, the cyclopropyl group, the methoxy group and the cyclopropyloxy group are optionally substituted by one or more R′; R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy; A is selected from the following groups: optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy; Y 1 For chemical bonds, CR 5 R 6 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl The methyl and morpholinyl groups are optionally substituted with one or more deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 5 and R 6 each independently represents a hydrogen atom, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, and the hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; or R 5 and R 6 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl and oxhexyl groups are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; Y 2 is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or a NR 7 , the acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl are optionally substituted by one or more deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino or dimethylamino; R 7 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Z is C(=O); L1 is NR 8 ; R 8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group; L2 is a chemical bond, O, CH or C(=O); E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, wherein the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted by one or more R e replace; R e is a deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 or P(O)(CH2CH3)2 , the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH3, SO2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, SO2NCH3, P(O)(CH3)2 and P(O)(CH2CH3)2 are optionally substituted with one or more F, Cl, hydroxyl, methyl, ethyl, isopropyl or cyclopropyl; G is selected from the following groups: R 1 Selected from the following groups: R 2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group; Most preferably, the compound represented by formula I is selected from the following compounds:

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient; Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays.

10. Use of the compound according to any one of claims 1 to 9 or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and / or the pharmaceutical composition according to claim 9 in treating diseases mediated by abnormal HER2; Preferably, the disease is a tumor disease; More preferably, the tumor disease includes: Head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, Renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

11. A method for treating a disease mediated by abnormal HER2, the method comprising administering to a patient in need thereof a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof and / or a pharmaceutical composition according to claim 9; Preferably, the disease is a tumor disease; More preferably, the tumor disease includes: Head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

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