WO2025051148A1 - Nitrogen-containing heteroaryl compound, and preparation method therefor and use thereof - Google Patents

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 preparation method and application thereof Technical Field

The present invention belongs to the field of pharmaceutical technology, and in particular relates to nitrogen-containing heteroaryl compounds and preparation methods and applications thereof.

Background Art

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 has tyrosine kinase activity. No ligand that can directly interact with HER2 has been found. HER2 can form heterodimers with other members of the ErbB family to activate the downstream MEK/ERK/MAPK pathway and PI3K/AKT bypass for signal transduction, ultimately promoting cell growth, proliferation and division.

Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been shown to be associated with many cancers, including breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, endometrial cancer and glioblastoma. The detection rates of HER2 overexpression in lung cancer, breast cancer, gastric cancer, bile duct cancer, ovarian cancer and endometrial cancer are approximately 2.5%, 15% to 25%, 20%, 20%, 27% and 18% to 80%, respectively.

The detection rate of HER2 mutation in non-small cell lung cancer is about 2%-4%, among which exon 20 insertion mutation accounts 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 mutation V659E (4.1%) and G660D (0.9%), and extracellular region mutation D277Y (1.9%), S310F (7.7%), S310Y (1.9%) and A466V (1.4%). In addition, studies have shown that cancer patients carrying HER2 abnormalities are more likely to develop central nervous system metastasis during the course of the disease. Approximately 47% of patients with HER2-mutated non-small cell lung cancer develop brain metastasis, which is associated with poor prognosis.

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) (enmetuzumab, demetuzumab).

Monoclonal antibodies and antibody-drug conjugates have poor selectivity for wild-type EGFR, and are large-molecule drugs that are not easy to penetrate the blood-brain barrier. In addition, some patients will develop drug resistance or relapse after using monoclonal antibodies (mAbs) for a period of time. Currently approved TKIs include selective TKI (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib) show moderate antitumor activity against wild-type HER2, but have poor effects against the most common HER2 exon 20 insertion mutation. In addition, non-selective TKIs have poor selectivity for wild-type EGFR and are prone to adverse reactions such as rash and diarrhea. Therefore, it is of great significance to develop HER2 inhibitors that are selective, can penetrate the blood-brain barrier, and have potential inhibitory effects on HER2 exon 20 insertion mutations.

Summary of the invention

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

The present invention is achieved through the following technical solutions.

In a first aspect, the present invention provides a compound having a structure as shown in the following formula I 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 ;

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 alkylthiol, _3-12 -membered cycloalkylthiol, 3-12-membered heterocyclylthiol, 3-12-membered cycloalkyl-C _1-6 alkylene-thiol or 3-12-membered heterocyclyl-C _1-6 alkylene-thiol, wherein the C 1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclylthiol, 3-12-membered cycloalkyl-C _1-6 alkylene-thiol or 3-12-membered heterocyclyl-C _1-6 alkylene-thiol _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 alkylthiol, 3-12 membered cycloalkylthiol, _3-12 membered heterocyclylthiol, 3-12 membered cycloalkyl-C _1-6 alkylene-thiol and 3-12 membered heterocyclyl-C _1-6 alkylene-thiol are optionally substituted with one or more R′;

Y ¹ is a chemical bond, CR ⁵ R ⁶ , a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R′;

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

Z is C(═O) or S(O) ₂ ;

L ₁ is NR ⁸ , O, CR ⁵ R ⁶ , S, S(O) or S(O) ₂ ;

L ₂ 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 ^Re ;

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;

^X1 is a chemical bond, N, CH, _CH2 , O, S, S(O) or S(O) ₂ ;

^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ;

^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time;

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

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

^R1 is a halomethyl group, a _C2-4 alkenyl group, a _C2-4 alkynyl group, an oxetane group or a _C4-6 cycloalkenyl group, wherein the _C2-4 alkenyl group, the _C2-4 alkynyl group, the oxetane group and the _C4-6 cycloalkenyl group are optionally substituted with one or more halogen, cyano, _C1-4 alkyl group, a halo-substituted _C1-4 alkyl group, a 3-12-membered cycloalkyl group, a deuterium atom, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, a 6-12-membered aryl group, a _C1-3 alkoxy- _C1-3 alkyl group, or ^NRaRb , wherein the _C1-4 alkyl group, the halo-substituted _C1-4 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 5-12-membered heteroaryl group, ^the 6-12-membered aryl group and the _C1-3 alkoxy- _C1-3 alkyl group are optionally substituted with one or more R′;

^R2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a _hydroxyl group, an amino group, a _C1-6 alkyl group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the _C2-4 alkenyl group, the _C2-4 alkynyl group, the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R's;

^R3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, _{a C1-6} alkyl group, a _{halogenated C1-6} alkyl group, a _C2-4 alkenyl group, a _C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered ^{cycloalkyloxy} group, _{a 3-12} -membered heterocyclyloxy group, ^{RcRdNC1-6alkylene} -oxy group, a _3-12 -membered cycloalkyl-C1-6alkylene-oxy group, a _3-12 -membered heterocyclyl-C1-6alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6alkyl )amino group, C(═O)NR ^c , NR ^c C(═O)R ^d or NR ^c C(═O)NR ^d , said hydroxy, 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, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, R ^c R ^d N _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 alkylthiol, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′;

^R4 is a hydrogen atom, a halogen, a cyano group, _an amino group, a _C1-6 alkyl group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a _C1-6 alkoxy group, a 3-12-membered cycloalkyl group, a _3-12 -membered heterocyclyl group, a C1-6 alkoxy group, a _3-12- membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 alkylthiol group, a _C1-6 alkylamino group or a di( _C1-6 alkyl)amino group, wherein the amino group, the _C1-6 alkyl group, the _C2-4 alkenyl group, the _C2-4 alkynyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the C1-6 alkoxy group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the _C1-6 alkylthiol group, the _C1-6 alkylamino group and the di( _C1-6 alkyl)amino group are optionally substituted with one or more R′;

^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-6 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, _{a 6-10-} membered aryl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12 -membered heterocyclyloxy group, a _C1-6 alkylmercapto group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, a cyano- _C1-6 alkyl-, a _{C1-6 alkoxy-C1-6} alkyl-, a 3-12-membered cycloalkyl- _C1-6 alkyl-, or a 3-12-membered heterocyclyl- _C1-6 alkyl-; the hydroxyl, amino group, _C1-6 alkyl group, a halogenated _C1-6 alkyl group, a C2-4 alkenyl group, a _C2-4 alkynyl group _2-4- alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, 5-12-membered heteroaryl, 6-10-membered aryl, C _1-6 alkoxy, halo-C _1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, C _{1-6 alkylthiol, 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- are optionally substituted with one or more R′;

or R ⁵ together with R ⁶ and the C atom to which they are attached form 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′;

^R7 is a hydrogen atom, a _C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a _C1-6 haloalkyl group, a 5-12-membered heteroaryl group or a 6-12-membered aryl group, wherein the _C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the _C1-6 haloalkyl group, the 5-12-membered heteroaryl group and the 6-12-membered aryl group are optionally substituted by one or more R's;

R ⁸ is a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a cyano-C _1-6 alkyl group or a hydroxy C _1-6 alkyl group;

^Ra and ^Rb are each independently a hydrogen atom, a _C1-4 alkyl group, a _C1-4 haloalkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl- _C1-4 alkyl group, a 3-12-membered heterocyclyl group, a _3-12 -membered cycloalkyl- _C1-4 alkyl group, a 3-12-membered heterocyclyl group- _C1-4 alkyl group, a _C1-4 alkoxy- _C1-4 alkyl group, or a deuterated C1-4 alkyl group, wherein the _C1-4 alkyl group, the C1-4 haloalkyl group, _{the 3-12} -membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl-C1-4 alkyl group, the 3-12-membered heterocyclyl group- _C1-4 alkyl group, the _C1-4 alkoxy- _C1-4 alkyl group and the deuterated _C1-4 alkyl group are optionally substituted by one or more R′;

or ^Ra , ^Rb and the N atom to which they are attached together form a 3-12 membered heterocyclic group, which is optionally substituted by one or more R';

R ^c and R ^d are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl group-C _1-6 alkyl group, or a 3-12-membered heterocyclyl group-C _1-6 alkyl group, wherein the C _1-6 alkyl group, the C _2-4 alkenyl group, the C _2-4 alkynyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl group-C _1-6 alkyl group, and the 3-12-membered heterocyclyl group-C _1-6 alkyl group are optionally substituted with one or more R′;

^Re is a deuterium atom, a halogen, a cyano group, a nitro group, a _C1-6 alkyl group, a _C2-6 alkenyl group, a _C2-6 alkynyl group, a _C2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group ^, a halogenated _C1-6 alkyl group, a halogenated _C1-6 alkoxy group, ^ORe1 , ^SRe1 , ^SORe1 , _SO2Re1 , C(＝O) ^Re1 , C(＝O ^{) NRe1} , C ⁽ ＝O) ^ORe1 , ^NRe1Re2 , NRe1C(＝O) ^Re2 , OC(＝O) ^Re1 , ^SONRe1 , _SO2NRe1 , NHS(O) ^{2Re1 , NHS(O)Re1, NRe1C(＝O)ORe2} _, ^{NRe1C ( ＝} O) ^NRe2 , -(O)(ORe1 ^{) e1} ) ₂ or P(O)(R ^e1 ) ₂ , the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C2-6 heteroalkenyl, _C2-6 heteroalkynyl, 3-12-membered saturated or unsaturated cycloalkyl, 3-12-membered saturated or unsaturated heterocyclyl, _C1-6 haloalkyl and _C1-6 haloalkoxy are optionally substituted by one or more R';

^Re1 and ^Re2 are each independently a hydrogen atom, a deuterium atom, a _C1-4 alkyl group, a halogenated _C1-4 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, or ^Re1 and ^Re2 together with the connected N atom form a 3-12-membered heterocyclic group;

R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C _1-6 alkyl group, _{a C 2-6 alkenyl} group, a C _2-6 alkynyl group, a halogenated C _1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group, a C _1-4 alkylamino group, a di(C _1-4 alkyl)amino group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkyl group, a halogenated C _1-6 alkoxy group or an oxo group (═O).

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

^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-4 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a _3-12- membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12- membered heterocyclyloxy group, ^RcRdN - ^C1-6 alkylene-oxy group, a 3-12-membered cycloalkyl- _C1-6 alkylene-oxy group, a 3-12-membered heterocyclyl- _C1-6 alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, C(=O) ^NRc , ^NRcC (=O) ^Rd or ^NRcC (=O) ^NRd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated C1-6 alkyl group, the _C2-4 alkenyl group, the C2-4 alkynyl group C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^c R ^d N c _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 alkylthio, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′;

R ^c and R ^d are each independently 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 ;

^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, _{a C1-6 alkyl} group, a halogenated _C1-4 alkyl group, a _C1-6 alkoxy group, a halogenated ^C1-6 alkoxy group, a 3-12-membered _{heterocyclyloxy} group, a ^{RcRdNC1-6alkylene} -oxy group, _{a 3-12} -membered heterocyclyl-C1-6alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group or a ^NRcC (=O) ^Rd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-4 alkyl group, the _C1-6 alkoxy group, the halogenated _C1-6 alkoxy group, the 3-12-membered _{heterocyclyloxy} ^group , the ^{RcRdNC1-6alkylene} -oxy group, the 3-12-membered heterocyclyl- _C1-6alkylene -oxy group, the _C1-6 alkylthiol group, the _C1-6 alkylamino group and the ^NRcC (=O)Rd ^d is 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 ;

^R3 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.

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

^R4 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 ;

^R4 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;

R' is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy.

In certain embodiments, in Formula I, A is _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy, or 3-12-membered heterocyclyl- _C1-6 alkylene-oxy, and the _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy, and 3-12-membered heterocyclyl- _C1-6 alkylene-oxy are 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, 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, 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. 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.

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.

In certain embodiments, in Formula I, Y ¹ is a chemical bond, CR ⁵ R ⁶ , a 3-12 membered cycloalkyl group, or a 3-12 membered heterocyclyl group, wherein the 3-12 membered cycloalkyl group and the 3-12 membered heterocyclyl group 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;

^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, a 5-12-membered heteroaryl group, a _6-10 -membered aryl group, a cyano- _C1-6 alkyl group, a C1-6 alkoxy- _C1-6 alkyl group, a _C1-6 alkylamino group or a 3-12-membered cycloalkyl- _C1-6 alkyl group; the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclic group, the 5-12-membered heteroaryl group, the 6-10-membered aryl group, the cyano- _C1-6 alkyl group, the _{C1-6 alkoxy-C1-6 alkyl} group, the _C1-6 alkylamino group and the 3-12-membered cycloalkyl-C1-6 _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 they are attached form 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 with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

Preferably, in Formula I, Y ¹ is a chemical bond, CR ⁵ R ⁶ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, and 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 are each independently 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 they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl or oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl and oxetanyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy.

In certain embodiments, in Formula I, Y ² is a chemical bond, a 3-12 membered heterocyclic group or NR ⁷ , wherein the 3-12 membered heterocyclic group is 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 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 NR ⁷ , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group; and R ⁷ is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group or a trifluoroethyl group.

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

In certain embodiments, in Formula I, L ₁ 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 hydroxy C _1-6 ethyl group;

Preferably, in Formula I, L ₁ is NR ⁸ ;

^R8 is a hydrogen atom, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group or an acetonitrile group.

In certain embodiments, in Formula I, L ₂ is a chemical bond, O, CH or C(═O).

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 with one or more ^Re ;

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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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 ^Re ;

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, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(═O)CH ₃ , _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 by one or more F, Cl, hydroxy, _methyl , _ethyl , isopropyl or cyclopropyl.

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;

-- is none or a single key;

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

^X1 is a chemical bond, N, CH, _CH2 , S, O, S(O) or S(O) ₂ ;

^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ;

^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time;

X ⁵ is a chemical bond, N, CH, CH ₂ , O or S;

^X6 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:

In certain embodiments, in Formula I, R ¹ is halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, and the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, oxetyl, cyclobutenyl, cyclopentenyl and cyclohexenyl are optionally substituted with one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, oxetyl, butylene oxide, deuterium atom, phenyl, pyridinyl or NR ^a R ^b , and the methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, oxetyl, butylene oxide, phenyl and pyridinyl are optionally substituted with one or more R ′;

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

or ^Ra, together with ^Rb and the N atom to which it is attached, forms 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, wherein the 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 or 2-azabicyclo[3.1.0]hexanyl group. Heterobicyclo[3.3.1]nonanyl, 2-azabicyclo[4.1.0]heptanyl and 2-azabicyclo[3.1.0]hexanyl are 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 is selected from the following groups:

In certain embodiments, in Formula I, R ² is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a C _1-4 alkyl group, or a 3-6 membered cycloalkyl group;

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.

In certain embodiments, in Formula I:

M is N or CR ³ ;

^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-4 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a _3-12- membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12- membered heterocyclyloxy group, ^RcRdN - ^C1-6 alkylene-oxy group, a 3-12-membered cycloalkyl- _C1-6 alkylene-oxy group, a 3-12-membered heterocyclyl- _C1-6 alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, C(=O) ^NRc , ^NRcC (=O) ^Rd or ^NRcC (=O) ^NRd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated C1-6 alkyl group, the _C2-4 alkenyl group, the C2-4 alkynyl group C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^c R ^d N c _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 alkylthio, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′;

R ^c and R ^d are each independently 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 ;

^R4 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 are optionally substituted with one or more R′;

Y ¹ is a chemical bond, CR ⁵ R ⁶ , a 3-12 membered cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the 3-12 membered cycloalkyl group and the 3-12 membered heterocyclyl group 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;

^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, a 5-12-membered heteroaryl group, a _6-10 -membered aryl group, a cyano- _C1-6 alkyl group, a C1-6 alkoxy- _C1-6 alkyl group, a _C1-6 alkylamino group or a 3-12-membered cycloalkyl- _C1-6 alkyl group; the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclic group, the 5-12-membered heteroaryl group, the 6-10-membered aryl group, the cyano- _C1-6 alkyl group, the _{C1-6 alkoxy-C1-6 alkyl} group, the _C1-6 alkylamino group and the 3-12-membered cycloalkyl-C1-6 _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 , wherein 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 ;

L ₁ 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 hydroxy C _1-6 ethyl group;

_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 ^Re ;

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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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;

^X1 is a chemical bond, N, CH, _CH2 , S, O, S(O) or S(O) ₂ ;

^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ;

^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time;

X ⁵ is a chemical bond, N, CH, CH ₂ , O or S;

^X6 is N, O, S or CH; or

R ¹ is a halomethyl group, a vinyl group, a propenyl group, a ethynyl group, a propynyl group, a butynyl group, a glycidyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group, wherein the halomethyl group, the vinyl group, the propenyl group, the ethynyl group, the propynyl group, the butynyl group, the glycidyl group, the cyclobutenyl group, the cyclopentenyl group or the cyclohexenyl group are optionally substituted with one or more F, Cl, a methyl group, an ethyl group, a cyclopropyl group, an acridinyl group, a pyrrolidinyl group, a piperidinyl group, a glycidyl group, a butylene oxide group, a deuterium atom, a phenyl group, a pyridinyl group or a NR ^a R ^b group, wherein the methyl group, the ethyl group, the cyclopropyl group, the acridinyl group, the pyrrolidinyl group, the piperidinyl group, the glycidyl group, the butylene oxide group, the phenyl group or the pyridinyl group are optionally substituted with one or more R ′;

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

or ^Ra, together with ^Rb and the N atom to which they are 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);

^R2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a _C1-4 alkyl group or a 3-6 membered cycloalkyl group.

In other specific embodiments, in Formula I:

M is N or CR ³ ;

^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, _{a C1-6 alkyl} group, a halogenated _C1-4 alkyl group, a _C1-6 alkoxy group, a halogenated ^C1-6 alkoxy group, a 3-12-membered _{heterocyclyloxy} group, a ^{RcRdNC1-6alkylene} -oxy group, _{a 3-12} -membered heterocyclyl-C1-6alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group or a ^NRcC (=O) ^Rd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-4 alkyl group, the _C1-6 alkoxy group, the halogenated _C1-6 alkoxy group, the 3-12-membered _{heterocyclyloxy} ^group , the ^{RcRdNC1-6alkylene} -oxy group, the 3-12-membered heterocyclyl- _C1-6alkylene -oxy group, the _C1-6 alkylthiol group, the _C1-6 alkylamino group and the ^NRcC (=O)Rd ^d is optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo;

X is N or CR ⁴ ;

^R4 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;

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, 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, 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 is a chemical bond, 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 are each independently 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 they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl, 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;

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

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

Z is C(═O) or S(O) ₂ ;

L ₁ 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 with one or more ^Re ;

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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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;

^R1 is selected from the following groups:

^R2 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.

In some further specific embodiments, in Formula I:

M is N or CR ³ ;

^R3 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 ;

^R4 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;

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 is a chemical bond, 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 are each independently 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 they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl, 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;

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

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

Z is C(＝O);

L ₁ 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 with one or more ^Re ;

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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl;

G is selected from the following groups:

^R1 is selected from the following groups:

^R2 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.

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

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:

(1) Compound I-1 undergoes coupling or substitution reaction with Compound I-2 to form Compound I-3;

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

(3) deprotecting compound I-5 to form compound I-6;

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

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

Compound I-3 and compound I-8 undergo coupling or substitution reaction to form a compound of formula I;

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

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

wherein M, X, A, E, G, Z, _L1 , _L2 , ^Y1 , ^Y2 , ^R1 and ^R2 are as defined above; H is a hydrogen atom; ^Xa is a chlorine atom; ^Xb is a bromine atom, an iodine atom or a hydroxyl group; ^Xc is hydrogen, halogen, OMs, -B(OH) ₂ or ^Xd is a bromine atom or an iodine atom; ^Ga is Boc, and ^Gb is Cl, OH or ^-OZR1 .

In a third aspect, the present invention provides a pharmaceutical composition comprising the above 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;

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.

In a fourth aspect, the present invention provides the use 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 a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, 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;

Preferably, the disease is a tumor disease;

More preferably, the tumor diseases include: 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.

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-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

The patient is preferably a mammal, and the mammal is preferably a human.

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

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.

The compounds or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions of the present invention can enter the body through any suitable route, such as oral, intravenous, intranasal, external, intramuscular, intradermal, transdermal or subcutaneous routes.

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

Suitable dosage forms include (but are not limited to) dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal absorption 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, such as those provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

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

Preferably, the HER2 gene mutation includes mutations in exons 18-21, transmembrane domains and extracellular regions; the mutations include point mutations, deletion mutations and insertion mutations;

More preferably, the exon 20 insertion mutation includes 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.

In certain embodiments, the compound or pharmaceutical composition of the present invention can be administered simultaneously with one or more other pharmacologically active substances, so that an additive or even synergistic effect can be achieved in vivo. For example, the compound of the present invention can be combined with other pharmacologically active substances into a pharmaceutical composition, or administered simultaneously as a separate composition, or administered sequentially as a separate composition. Other pharmacologically active substances that can be used simultaneously with the compounds of the present invention for the treatment of cancer include but are not limited to: 1) EGFR family inhibitors, single/double antibodies or ADCs, such as osimertinib, ametinib, vometinib, befortinib, olmutinib, Lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emmetuzumab, detrastuzumab, etc.; 2) downstream pathway or other pathway target inhibitor single/double antibodies or ADCs, etc., the targets include but are not limited to MEK, RET, PI3K, mTOR, c-Met, PARP or mitotic kinase inhibitors (such as CDK4/6), etc. 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, carbapenem, etc. vaccinia vaccine, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carmustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, daunomycin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, Niposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole, leucovorin, pentostatin, mithramycin, procarbazine, raltitrexed, porfir sodium, rituximab, streptozotocin, suramin, leuprolide, levamisole, cyclohexyl lomustine, nitrogen mustard, medroxyprogesterone, megestrol acetate, melphalan, mercaptopurine, sodium thioethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, norco Dadazole, octreotide, paclitaxel, pamidronate, thioguanine, triamidite, methyl chloride, topotecan titanocene, retinoic acid, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

In certain embodiments, the compounds provided by the present invention can be used simultaneously with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents for reversing multidrug resistance of tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

In certain embodiments, the compounds provided by the invention can be used simultaneously with non-chemical methods to treat cancer. In certain embodiments, the compounds provided by the invention can be used simultaneously with radiotherapy. In certain embodiments, the compounds provided by the invention can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy or several of the above therapies.

The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

It is particularly important to point out that similar substitutions and modifications made to the present invention are obvious to those skilled in the art, and they are all considered to be included in the present invention. Relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments.

If no specific conditions are specified in the present invention, the process is carried out under conventional conditions or conditions recommended by the manufacturer. The raw materials or excipients used, as well as the reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be obtained commercially.

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.

Indicates the connection site.

The minimum and maximum carbon atom content of the hydrocarbon group is indicated by a prefix, for example, the prefix (C _ab ) 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 from 1 to 6 carbon atoms. The alkyl group may be branched or straight chain.

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

"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. Preferably C _1-8 alkyl. More preferably C _1-6 alkyl. More preferably C _1-4 alkyl.

The alkyl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, a cyano group, a nitro group, an azido group, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C _1-10 alkyl group, a halogenated C _1-10 alkoxy group, a deuterated C _1-10 alkyl group, a deuterated C _1-10 alkoxy group, a 6-10-membered aryl group, a 5-10-membered heteroaryl group, an oxo (═O), a —C _0-6 alkyl-OR ^e1 , a —C _0-6 alkyl-SR ^e1 , a —C 0-6 alkyl-SOR ^e1 , a —C _0-6 alkyl-SO ₂ R ^e1 , a —C _0-6 alkyl-C(═O)R ^e1 , a —C _0-6 alkyl- _-C0-6 alkyl-C(═O)NR ^e1 , _-C0-6 alkyl-C(═O)OR ^e1 , _-C0-6 alkyl-NR ^e1 R ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)R ^e2 , _-C0-6 alkyl-OC(═O)R ^e1 , _-C0-6 alkyl-SONR ^e1 , _-C0-6 alkyl-SO ₂ NR ^e1 , _-C0-6 alkyl-NHS(O) ₂ R ^e1 , _-C0-6 alkyl-NHS(O)R ^e1 , _-C0-6 alkyl-NR ^e1 C(═O)OR ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)NR ^e2 , _-C0-6 alkyl-(O)(OR ^e1 ) ₂ , and _-C0-6 alkyl-P(O)(R ^e1 ) ₂ .

"Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group that can be combined with other groups. Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, a 3-8-membered cycloalkyl group. More preferably, a 3-6-membered cycloalkyl group. More preferably, a 3-4-membered cycloalkyl group. Polycyclic hydrocarbon groups include linked rings, spiro rings, condensed rings, or bridged ring cyclic aliphatic hydrocarbon groups, including but not limited to the following groups:

"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, 3-8-membered cycloalkenyls. More preferably, 3-6-membered cycloalkenyls. More preferably, 5-6-membered cycloalkenyls. Polycyclic cycloalkenyls include linked rings, spiro rings, condensed rings or bridged ring cycloalkenyls. Including but not limited to the following groups:

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

"Alkenyl" refers to a straight chain, branched or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably _C2-6 alkenyl. More preferably _C2-4 alkenyl.

"Alkynyl" refers to a straight chain, 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. Preferably _C2-6 alkynyl. More preferably _C2-4 alkynyl.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

"Haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogens have been replaced by the same or different halogens, including but not limited to _-CH2Cl , _-CHF2 , _-CH2CF3 , _-CH2CC13 , _{perfluoroalkyl} (eg, _-CF3 ), _and the like.

"Alkylamino" refers to NH ₃ substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino and the like.

"Dialkylamino" refers to a group having the structure N(C _1-6 alkyl) ₂ , including but not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, and the like.

"Aryl" refers to a monocyclic or polycyclic carbon ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, indenyl. Preferably, it is a 6-10 membered monocyclic or bicyclic aromatic group. More preferably, it is phenyl or naphthyl. Most preferably, it is phenyl.

"Heterocyclyl" refers to a group of 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 systems include fused, bridged or spirocyclic 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:

The heterocyclic group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, a cyano group, a nitro group, an azido group, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C _1-10 alkyl group, a halogenated C _1-10 alkoxy group, a deuterated C _1-10 alkyl group, a deuterated C _1-10 alkoxy group, a 6-10-membered aryl group, a 5-10-membered heteroaryl group, an oxo (═O), a —C _0-6 alkyl-OR ^e1 , a —C _0-6 alkyl-SR ^e1 , a —C _0-6 alkyl-SOR e1 , a —C 0-6 alkyl-SO ₂ R ^e1 , a —C _0-6 alkyl-C( ^═O )R ^e1 , a —C _0-6 alkyl- _-C0-6 alkyl-C(═O)NR ^e1 , _-C0-6 alkyl-C(═O)OR ^e1 , _-C0-6 alkyl-NR ^e1 R ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)R ^e2 , _-C0-6 alkyl-OC(═O)R ^e1 , _-C0-6 alkyl-SONR ^e1 , _-C0-6 alkyl-SO ₂ NR ^e1 , _-C0-6 alkyl-NHS(O) ₂ R ^e1 , _-C0-6 alkyl-NHS(O)R ^e1 , _-C0-6 alkyl-NR ^e1 C(═O)OR ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)NR ^e2 , _-C0-6 alkyl-(O)(OR ^e1 ) ₂ , and _-C0-6 alkyl-P(O)(R ^e1 ) ₂ .

"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, and the remaining ring atoms are 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, quinolyl, isoquinolyl, benzimidazolyl or benzothiazolyl.

The heteroaryl group is optionally substituted or unsubstituted, and the substituted substituent is preferably one or more of the following groups: a deuterium atom, a halogen, a cyano group, a nitro group, an azido group, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C _1-10 alkyl group, a halogenated C _1-10 alkoxy group, a deuterated C _1-10 alkyl group, a deuterated C _1-10 alkoxy group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, an oxo (═O), a —C _0-6 alkyl-OR ^e1 , a —C _0-6 alkyl-SR ^e1 , a —C _0-6 alkyl-SOR ^e1 , a —C _0-6 alkyl-SO ₂ R ^e1 , a —C 0-6 alkyl-C(═O)R ^e1 , a —C _0-6 alkyl- _-C0-6 alkyl-C(═O)NR ^e1 , _-C0-6 alkyl-C(═O)OR ^e1 , _-C0-6 alkyl-NR ^e1 R ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)R ^e2 , _-C0-6 alkyl-OC(═O)R ^e1 , _-C0-6 alkyl-SONR ^e1 , _-C0-6 alkyl-SO ₂ NR ^e1 , _-C0-6 alkyl-NHS(O) ₂ R ^e1 , _-C0-6 alkyl-NHS(O)R ^e1 , _-C0-6 alkyl-NR ^e1 C(═O)OR ^e2 , _-C0-6 alkyl-NR ^e1 C(═O)NR ^e2 , _-C0-6 alkyl-(O)(OR ^e1 ) ₂ , and _-C0-6 alkyl-P(O)(R ^e1 ) ₂ .

"Bridged ring" refers to a polycyclic group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and 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 SO ₂ . Preferably, it has 7-10 rings.

"Spirocyclic ring" refers to a polycyclic group in which any two rings share a carbon atom, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and 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 SO ₂ . Preferably, the ring has 5-10 rings.

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

According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

A cyclic group can be bonded to another group in a variety of ways. If the bonding mode is not specified, it is meant to include all possible modes. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

"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. Preferably C _1-8 alkoxy. More preferably C _1-6 alkoxy. More preferably C _1-4 alkoxy.

"Cycloalkoxy" refers to -O-cycloalkyl, wherein the cycloalkyl is as described above. Preferably, C _3-8 cycloalkoxy. Including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and other similar groups.

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

"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts, which 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, aminosulfonic acid, phosphoric acid and nitric acid. The organic acids are such as 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, 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.

"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.

“N-oxide” means that when a compound contains an amine functional group or a heteroaryl compound containing N atoms, one or more N atoms can be oxidized to form a compound containing N ⁺ , preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl compound containing N.

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

"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.

"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutically acceptable carriers, excipients or diluents. The purpose of a pharmaceutical composition is to facilitate the process of administration to an animal. A pharmaceutical composition may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH regulators and buffers, toxicity regulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

"Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which participates in loading or delivering the compounds of the present 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 excessively toxic or has side effects and can be used to contact animal tissues.

Some pharmaceutically acceptable carrier materials 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, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (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) (11) glycols, such as propylene glycol; (12) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) lipids, such as ethyl oleate and ethyl laurate; (14) agarose; (15) buffers, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) sterile pyrogen-free water; (18) Ringer's solution; (19) alcohols, such as ethanol and propanol; (20) phosphate buffer; (21) other non-toxic and compatible substances in pharmaceutical dosage forms, such as acetone.

Each pharmaceutically acceptable carrier should be compatible with other components, for example, forming a preparation 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 of organisms, and with a reasonable benefit-risk ratio.

The pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage form (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage form (e.g., aqueous solution, emulsion, elixir, syrup, etc.). As is well known, it can be prepared according to conventional techniques, for example, as provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

DETAILED DESCRIPTION

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

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

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

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 in sequence, and stirred at room temperature for 1 h. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and 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 chromatography with ethyl acetate/petroleum ether = 0-76% as the eluent gradient elution 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] ⁺ . Potassium carbonate can also be replaced by cesium carbonate or sodium carbonate in this step.

Step 2: 3-Chloro-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline

5-(2-chloro-4-nitrophenoxy)-1-methyl-1H-benzimidazole (1.8 g, 5.9 mmol) was dissolved in a mixed solution 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 in sequence, nitrogen was replaced, the temperature was raised to 60°C and stirred for 1 h. The reaction solution was cooled to room temperature. Filtered, the filtrate was concentrated under reduced pressure, water (20 mL) was added to the residue, extracted with dichloromethane (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 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] ⁺ .

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

3-Chloro-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (500 mg, 1.8 mmol) was dissolved in isopropanol (5 mL), 5-iodo-4-chloropyrimidine (439 mg, 1.8 mmol) was added, and the mixture was heated to 80°C and stirred for 1 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 (0-10%) as the eluent by gradient elution 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] ⁺ .

Preparation of intermediates A2-A8, A19-A26

Using commercially available aryl/heteroaryl phenols and halogenated aryl/heteroaryl nitro compounds or halogenated heteroaryl and aryl/heteroaryl nitrophenol compounds as raw materials, the synthesis method of intermediate A1 (or using 1,4-dioxane as solvent, N,N-diisopropylethylamine or triethylamine as catalyst, and reaction conditions of 60-90° C.) was used to prepare intermediates A2-A8 and A19-A26. As shown in Table 1.

Table 1 Intermediates A2-A8, A19-A26

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

3-Methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (298.6 mg, 1.2 mmol) was dissolved in anhydrous ethanol (5 mL), 4-chloro-5-iodo-6-methylpyrimidine (300 mg, 1.2 mmol) and methanesulfonic acid (11.3 mg, 0.12 mmol) were added, and the mixture was heated to 70°C and stirred for 1 h. The reaction mixture was cooled to room temperature, water (5 mL) was added to quench the reaction, sodium bicarbonate was used to adjust the mixture to alkalinity, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and 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 chromatography with methanol/dichloromethane = 0-10% as the eluent gradient elution 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] ⁺ .

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

At 0°C, 5-bromo-6-chloropyrimidin-4-amine (500 mg, 2.4 mmol) was dissolved in tert-butanol (8 mL), nitrogen was replaced, 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, and the temperature was raised to 100°C and stirred for 1 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by chromatography with methanol/dichloromethane = 0-10% as the eluent gradient elution 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] ⁺ .

Intermediate A11. Preparation of 5-bromo-N ⁴ -(3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)pyrimidine-2,4-diamine

In a 40 mL microwave tube, 5-bromo-2-chloro-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidine-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 to 100°C for 2 h under microwave heating. The mixture was cooled to room temperature and 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] ⁺ .

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

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, nitrogen was replaced, 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 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 chromatography with methanol/dichloromethane = 0-15% as the eluent to obtain 5-iodo-N ⁴ -(2- methoxyethyl)-N ⁶ -(3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)pyrimidine-4,6-diamine (brown yellow solid, 125 mg, 38.6%). MS (ESI ⁺ ) m/z=531.1 [M+H] ⁺ .

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

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 removed by distillation under reduced pressure, and the residue was separated and purified by silica gel chromatography with methanol/dichloromethane = 10% as the eluent to obtain 5-iodo-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)-6-methylthiopyrimidin-4-amine (light yellow solid, 450 mg, 87.9%). MS (ESI ⁺ ) m/z = 504.0 [M+H] ⁺ .

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

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

3-Methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (2g, 7.9mmol) was dissolved in toluene (40mL), and paraformaldehyde (0.28g, 9.48mmol) and palladium carbon (0.84g, 7.9mmol) were added. The nitrogen was replaced, and the temperature was raised to 60°C and stirred for 2h. Water (50mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL×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 with methanol/dichloromethane = 0-10% as the eluent to obtain N,3-dimethyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)aniline (off-white solid, 900mg, 38.4%). MS (ESI ⁺ ) m/z = 268.2 [M+H] ⁺ .

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

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 raw material according to the method for synthesizing intermediate A9. MS (ESI ⁺ ) m/z=472.1[M+H] ⁺ .

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

3-Methyl-4-((1-methylbenzimidazol-5-yl)oxy)aniline (1.7 g, 6.9 mmol) was dissolved in acetic acid (20 mL), 4-chloropyrimidin-5-ol (1.5 g, 11.5 mmol) was added, and the temperature was raised to 60°C and stirred for 2 h. After cooling to room temperature, water (20 mL) was added to quench the reaction, 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 to obtain a crude product. The crude product was separated and 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] ⁺ .

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

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. At 0°C, tert-butyl nitrite (1.2g, 11.9mmol) was added, and the temperature was raised to room temperature and stirred for 1h. Water (20mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20mL×3). The organic phases were combined and 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 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] ⁺ .

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

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

Dissolve 6-(difluoromethyl)pyrimidin-4-ol (800 mg, 5.5 mmol) in acetonitrile (10 mL) in a 40 mL single-mouth bottle, and add N-bromosuccinimide (1.95 mg, 11.0 mmol) under ice bath. Replace nitrogen, heat to 70 °C and stir for 1 h. Cool the reaction solution to room temperature and concentrate under reduced pressure. The residue was separated and purified by silica gel chromatography with ethyl acetate/petroleum ether = 0-80% as 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] ⁺ .

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

Add 5-bromo-6-(difluoromethyl)pyrimidin-4-ol (1.2 g, 5.3 mmol) to a 40 mL single-mouth bottle, slowly add phosphorus oxychloride (10 mL) dropwise under ice bath, replace nitrogen, heat to 90 ° C and stir for 1 hour. Cool the reaction solution to room temperature and concentrate under reduced pressure to obtain 5-bromo-4-chloro-6-(difluoromethyl)pyrimidine (yellow oil, 1.2 g, 92.42%, crude product).

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

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

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

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

At 0°C, in a 100 mL eggplant-shaped bottle, dissolve 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (1 g, 3.9 mmol) in 30% concentrated sulfuric acid (10 mL), and add sodium nitrite (409 mg, 5.9 mmol) under ice-salt bath. Aqueous solution, stirred at 0℃ for 20min, then slowly added 10% concentrated sulfuric acid (0.5～1mL), heated to 100℃ and stirred for 1h. The reaction mixture was cooled to room temperature, neutralized with sodium bicarbonate to pH=7～8, extracted with ethyl acetate (50mL×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 with 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, 974mg, 97.0%). MS (ESI ⁺ ) m/z＝255.2[M+H] ⁺ .

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

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 to a 40 mL reaction bottle 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 the 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] ⁺ .

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

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, and the temperature was raised to 80 ° C and stirred for 2 h. After the reaction was complete, the temperature was lowered to room temperature, water (10 mL) was added to quench the reaction, the mixed solution was extracted with dichloromethane/methanol (3/1 v/v, 30 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography using methanol/dichloromethane (15%) as an eluent to obtain imidazo[1,2-a]pyridine-7-ol (yellow oil, 1.0 g, 73.2%). MS (ESI ⁺ ) m/z = 157.1 [M + Na + H] ⁺ .

Step 2: Dissolve imidazo[1,2-a]pyridine-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) in turn. Heat to 80°C and stir for 3 h. After the reaction is complete, cool to room temperature, add water (30 mL) to the reaction solution, extract the mixture with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography with methanol/dichloromethane (15%) as the eluent to obtain 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine (light yellow solid, 1.1 g, 55.0%). MS(ESI ⁺ )m/z=270.0[M+H] ⁺ .

Step 3: Dissolve 7-(2-methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (1.0 g, 3.71 mmol) in acetonitrile (15 mL), 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 × 3), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography with 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] ⁺ .

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

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

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 sequentially into a 100 mL reaction bottle, 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), filtered, and the filtrate 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 to obtain a crude product. The crude product was separated and purified by silica gel chromatography with dichloromethane/methanol (0-10%) as the eluent gradient elution 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] ⁺ .

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

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

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

In a 100mL single-mouth bottle, 1-tert-butyloxycarbonyl-azetidine-2-carboxylic acid methyl ester (1.0g, 4.7mmol) was dissolved in methanol (15mL), sodium borohydride (351.5mg, 9.4mmol) was added under ice bath, and the temperature was raised to room temperature and stirred for 1h. Water (10mL) was added under ice bath to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (20mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (white solid, 700mg, crude product).

Step 2: tert-Butyl 2-formylazetidine-1-carboxylate

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 sodium bicarbonate aqueous solution (50 mL) to quench the reaction, filter, extract the filtrate with dichloromethane (200 mL×3), combine the organic phases, wash with saturated sodium bicarbonate (50 mL), then dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain tert-butyl 2-formylazetidine-1-carboxylate (white solid, 2.4 g, 80.9%).

Step 3: tert-Butyl 2-ethynylazetidine-1-carboxylate

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

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

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

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

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

Dissolve (2S)-2-methyl-1-tert-butyloxycarbonylpyrrolidine-2-carboxylic acid (500 mg, 2.2 mmol) in dichloromethane (10 mL), add 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) in turn, quickly add 4,4,5,5-tetramethyl-1,3,2-dioxaborane (307.0 mg, 2.4 mmol) at room temperature, replace with nitrogen, and stir at room temperature for 10 min. After the reaction is complete as monitored by TLC, add water (5 mL) to quench the reaction, extract the mixed solution with dichloromethane (10 mL×3), combine the organic phases, dry them over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography with ethyl acetate/petroleum ether (0-50%) as the eluent 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] ⁺ .

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

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

Preparation of intermediates B4-B16

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

Table 2 Intermediates B4-B16

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

Step 1: tert-Butyl 2-formyl-5-methylpiperidin-1-carboxylate

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), keep 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, extract the mixed solution with ethyl acetate (40 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography with 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] ⁺ .

Step 2: tert-Butyl 2-ethynyl-5-methylpiperidine-1-carboxylate

Using tert-butyl 2-formyl-5-methylpiperidine-1-carboxylate as raw material, tert-butyl 2-ethynyl-5-methylpiperidine-1-carboxylate (yellow oil, 280 mg, 64.0%) was prepared according to the second step synthesis method of intermediate B1.

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

Using tert-butyl 2-methylpiperidine-1-carboxylate as raw 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.

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

Dissolve tert-butyl (2,2,2-trifluoroethyl)carbamate (300 mg, 1.5 mmol) in tetrahydrofuran (5 mL), replace nitrogen, 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, stir at room temperature for 3 h. After the reaction is completed by TLC monitoring, add water (5 mL) to quench the reaction, extract the mixed solution with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain tert-butyl propyl-2-yn-1-yl (2,2,2-trifluoroethyl)carbamate (colorless oil, 280 mg).

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

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

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

Using tert-butyl (1-ethynylcyclopropyl)carbamate as raw material, tert-butyl (1-ethynylcyclopropyl)(methyl)carbamate (colorless oil) was prepared according to the synthetic method of intermediate B19.

Intermediate B22. Preparation of tert-butyl (1-phenylpropyl-2-alkynyl-1-yl)carbamate

1-Phenylprop-2-yn-1-amine (105 mg, 0.8 mmol) was dissolved in dichloromethane (5 mL), triethylamine (161.9 mg, 1.6 mmol) and di-tert-butyl dicarbonate (349.2 mg, 1.6 mmol) were added, and 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 × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography with ethyl acetate/petroleum ether = 0-50% as the eluent to obtain (1-phenylpropyl-2-ynyl-1-yl)carbamic acid tert-butyl ester (light yellow oil, 135.1 mg, 73.7%). MS (ESI ⁺ ) m/z = 331.3 [M + H] ⁺ .

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

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

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

Triethyl phosphonoacetate (2.3 g, 10.0 mmol), tetrahydrofuran (20 mL), potassium tert-butoxide (3.4 g, 30.1 mmol) and (2S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.0 mmol) were added to a 40 mL reaction bottle in sequence, nitrogen was replaced, and the mixture was stirred at room temperature for 6 h. After the reaction was completed as monitored by TLC, water (50 mL) was added to quench the reaction, 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 to obtain a crude product. The crude product was separated and purified by silica gel chromatography with ethyl acetate/petroleum ether = 0-50% as the eluent to obtain (2S)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (yellow oil, 2.6 g, 93.3%). MS(ESI ⁺ )m/z=270.5[M+H] ⁺ .

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

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) to a 50 mL reaction bottle and stir at room temperature for 1 h. After the reaction is complete as monitored by TLC, concentrate under reduced pressure to obtain 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] ⁺ .

Step 3: 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoic acid ethyl ester

3-((2S)-pyrrolidin-2-yl)prop-2-enoic acid ethyl ester (1.0g, 5.9mmol) was dissolved in N,N-dimethylformamide (10mL), sodium hydride (70.9mg, 3.0mmol) was added under ice bath, stirred for 30min, then iodomethane (838.8mg, 5.9mmol) was added, nitrogen was replaced, and stirred at room temperature for 1h. After TLC monitoring, water (50mL) was added to quench the reaction, and ethyl acetate (50mL×3) was used for extraction. The organic phases were combined and 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 chromatography with ethyl acetate/petroleum ether = 0-50% as eluent to obtain 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoic acid ethyl ester (yellow oil, 279.0mg, 25.0%).

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

To a 40 mL reaction bottle, ethyl 3-((2S)-1-methylpyrrolidin-2-yl)prop-2-enoate (270 mg, 1.5 mmol), a mixed solution of tetrahydrofuran/methanol/water (9 mL, 1/1/1) and lithium hydroxide (35.3 mg, 1.5 mmol) were added in sequence, nitrogen was replaced, and the mixture was stirred at room temperature for 4 h. After concentration under reduced pressure, water (50 mL) was added to the residue, pH was adjusted to 2 with HCl 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 to obtain a crude product. The crude product was separated and purified by silica gel chromatography with 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] ⁺ .

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

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] ⁺ .

Intermediate C3. Preparation of 4-(dimethylamino)but-2-ynoic acid

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), stir for 0.5 h, and add dry ice (2.0 g) at this temperature. Slowly warm to room temperature and continue stirring for 0.5 h. Concentrate under reduced pressure at low temperature and then freeze-dry. The crude product is separated and purified by high performance liquid chromatography (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%-50% acetonitrile 8 min; wavelength: 254/220 nm) to obtain 4-(dimethylamino)but-2-ynoic acid (yellow oil, 100 mg, 16.4%). MS(ESI ⁺ )m/z=128.3[M+H] ⁺ .

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

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 h, then add dry ice and continue stirring for 2 h. 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] ⁺ .

Preparation of intermediates C5-C6

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

Table 3 Intermediates C5-C6

The fourth group of preparation examples: preparation of intermediates D1-D3

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

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

Under nitrogen protection at 0℃, tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.0g, 5.7mmol) was dissolved in dichloromethane (10mL), triethylamine (1.7g, 17.1mmol) was added, and then methylsulfonyl chloride (1.3g, 11.4mmol) was added dropwise, and stirred at 0℃ for 2h. Water (10mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50mL×3). The organic phases were combined and 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 chromatography with petroleum ether/ethyl acetate = 50% as the eluent to obtain 2-((tert-butyloxycarbonyl)(methyl)amino)ethyl methanesulfonate (yellow oil, 1.0g, 69.2%). MS (ESI ⁺ ) m/z = 254.1 [M+H] ⁺ .

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

Under nitrogen protection, 2-((tert-butyloxycarbonyl)(methyl)amino)ethyl methanesulfonate (1.0 g, 3.9 mmol) was dissolved in N,N-dimethylformamide solution (10 mL), cesium carbonate (2.6 g, 7.8 mmol) and 4-aminopyrimidin-5-ol (439.0 mg, 3.9 mmol) were added in sequence, and the temperature was raised to 60°C and stirred overnight. After cooling to room temperature, ice water (20 mL) was added to quench the reaction, 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 and purified by silica gel chromatography with petroleum ether/ethyl acetate = 50% as the eluent to obtain 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] ⁺ .

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

Using (3-hydroxycyclopentyl)carbamic acid tert-butyl ester as raw material, the synthesis method of intermediate D1 was used to prepare (3-(4-aminopyrimidin-5-yl)oxy)cyclopentyl)carbamic acid tert-butyl ester (yellow solid, 21.2 g, 94.9%). MS (ESI ⁺ ) m/z = 295.1 [M+H] ⁺ .

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

Dissolve tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate (1g, 3.4mmol) in N,N-dimethylformamide (10mL), add potassium carbonate (1.3g, 10.2mmol) and 4-aminopyrimidin-5-ol (541.0mg, 3.4mmol), heat to 100℃ and stir for 1h. Cool to room temperature, add water (20mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography with petroleum ether/ethyl acetate = 0-76% as eluent to obtain tert-butyl 3-(((4-aminopyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (yellow solid, 0.9g, 81.9%). MS (ESI ⁺ ) m/z = 295.1 [M+H] ⁺ .

The fifth group of preparation examples: preparation of intermediates E1-E11

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

Step 1: Ethyl 4-chloropyrimidine-5-carboxylate

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] ⁺ .

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

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), Pd ₂ (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 nitrogen, heat to 100°C and stir for 2 h. The mixed solution is cooled to room temperature, filtered, the filter cake is washed with ethyl acetate (100 mL×3), and the filtrate is concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography with methanol/dichloromethane = 0-10% as the eluent to obtain 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] ⁺ .

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

At 0°C, 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), and a solution of lithium hydroxide (119 mg, 5.0 mmol) in water (5 mL) was added, and stirred at room temperature for 2 h. 1N hydrochloric acid was added to adjust the pH to 2-4, and the mixed solution was extracted with dichloromethane/methanol = 10/1 (50 mL×3), and 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 chromatography 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] ⁺ .

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

At 0°C, 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), and N,N-diisopropylethylamine (946.9 mg, 7.5 mmol), 2-amino-3-hydroxypropionic acid methyl ester hydrochloride (683.8 mg, 4.5 mmol) and benzotriazole-N,N,N',N'- Tetramethyluronium hexafluorophosphate (HBTU, 1.1 g, 3.0 mmol) 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), 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 = 10% as the eluent to obtain (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] ⁺ .

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

Under nitrogen protection, (4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (DAST, 101.5 mg, 0.6 mmol) was added at -78°C, and stirred at room temperature for 2 h. After the reaction was completed, water (30 mL) was added at 0°C to quench the reaction, and the mixed solution was extracted with dichloromethane/methanol = 10/1 (30 mL×3), and 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 with methanol/dichloromethane = 10% as the eluent to obtain methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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] ⁺ .

Step 6: 2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylic acid methyl ester

Under nitrogen protection, 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-diazobispiro[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, and the mixture was heated 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 obtain Methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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] ⁺ .

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

Using 3-methyl-4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)aniline and ethyl 4-chloropyrimidine-5-carboxylate as raw materials, 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 according to the preparation method of intermediate E1. MS (ESI ⁺ ) m/z = 444.6 [M+H] ⁺ .

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

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

Under nitrogen protection, 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), and N,N-diisopropylethylamine (5.2 g, 40 mmol) and 7-chloropyrazole were added. [1,5-a]pyrimidine-6-carboxylic acid ethyl ester (3 g, 13.3 mmol), heated to 80 ° C and stirred for 2 h. Cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography with methanol/dichloromethane = 20% as eluent to obtain 7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)aminopyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (off-white solid, 5 g). MS (ESI ⁺ ) m/z = 443.1 [M+H] ⁺ .

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

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

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

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) was dissolved in N,N-dimethylformamide (60 mL), L-threonine methyl ester hydrochloride (1 g, 8.7 mmol) and N,N-diisopropylethylamine (1.1 g, 8.7 mmol) were added, the mixture was cooled to 0°C, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (HATU, 3.3 g, 8.7 mmol) was added, and the mixture was heated to room temperature and stirred for 2 h. Concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain (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] ⁺ .

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

Dissolve (7-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonyl)serine methyl ester (300 mg, 0.6 mmol) in dichloromethane (1 mL), add 4-dimethylaminopyridine (DMAP, 213 mg, 1.8 mmol), add perfluorobutylsulfonyl fluoride (351 mg, 1.2 mmol) dropwise with stirring, and stir at room temperature for 24 h. Dichloromethane (50 mL) was added to dilute, and the mixture was washed with sodium bicarbonate aqueous solution (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 2-(7-((3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-4,5-dihydrooxazole-4-carboxylic acid methyl ester (yellow oil, 190 mg). MS (ESI ⁺ ) m/z = 498.1 [M+H] ⁺ .

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

Using 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 as raw material, 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 (light yellow solid, 476 mg) was synthesized according to the sixth step method of synthetic intermediate E1. MS (ESI ⁺ ) m/z＝496.1[M+H] ⁺ .

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

Under nitrogen protection, 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), and 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 in sequence, and 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 with methanol/dichloromethane = 10% as the eluent to obtain 5-methyl-2-(4-((3-methyl-4-((1- Methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxylate (light yellow solid, 200 mg, 19.0%). MS (ESI ⁺ ) m/z = 471.0 [M+H] ⁺ .

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

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

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

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) in turn, cool to 0°C, slowly add HATU (2.6 g, 6.8 mmol) in DMF (5 mL), 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 residue was separated 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] ⁺ .

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, concentrate the reaction solution under reduced pressure, and separate the residue by silica gel column chromatography with methanol/dichloromethane (1/10) as the eluent to obtain (4-((4-methoxybenzyl)amino)serine 4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carbonyl)serine methyl ester (light yellow solid, 1.3 g, 81.0%). MS (ESI ⁺ ) m/z = 612.4 [M+H] ⁺ .

Step 3 and Step 4: Using (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 starting material, 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 (light yellow solid, 620 mg, 57.0%) was prepared according to the method of Step 5 and Step 6 of Synthesis Intermediate E1. MS (ESI ⁺ ) m/z = 592.3 [M+H] ⁺ .

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

Step 1: Dissolve 5-bromo-4-chloropyrimidine (10.0 g, 51.70 mmol) in N,N-dimethylformamide (100 mL), 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 mixed solution with ethyl acetate (200 mL × 3), wash the combined organic phases with a saturated sodium chloride solution (200 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography with ethyl acetate/petroleum ether (40%) as the eluent to obtain 5-bromo-4-(methylthio)pyrimidine (light yellow oil, 6 g, 56.6%). MS (ESI ⁺ ) m/z = 207.0 [M + H] ⁺ .

Step 2: Under nitrogen protection, 5-bromo-4-(methylthio)pyrimidine (5.0 g, 24.38 mmol) was dissolved in 1,4-dioxane (70 mL), and Pd(dppf)Cl ₂ (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 in sequence. 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 mixed solution was extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with a saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 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] ⁺ .

Step 3: Under nitrogen protection, 4-methylthio-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (6.0 g, 23.80 mmol) was dissolved in a mixture of 1,4-dioxane and water (4/1 v/v, 62.5 mL), and 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). Heat to 80 °C and stir for 3 h. After the reaction is complete, cool to room temperature, add water (100 mL) to the reaction solution, extract the mixed solution with ethyl acetate (100 mL × 3), wash the combined organic phases with saturated sodium chloride solution (100 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography with ethyl acetate/petroleum ether (50%) as the eluent to obtain ethyl 2-(4-(methylthio)pyrimidin-5-yl)oxazole-4-carboxylate (light yellow solid, 2 g, 31.7%). MS (ESI ⁺ ) m/z = 266.0 [M + H] ⁺ .

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 residue is separated by silica gel column chromatography using petroleum ether (100%) as 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] ⁺ .

Step 5: Dissolve ethyl 2-(4-chloropyrimidin-5-yl)oxazole-4-carboxylate (473.4 mg, 1.87 mmol) in isopropanol (20 mL), 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, concentrate the reaction solution under reduced pressure, and separate the residue by silica gel column chromatography with methanol/dichloromethane (1/10) as eluent to obtain 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] ⁺ .

Preparation of intermediates E8-E10.

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 raw materials, intermediates E8-E10 were prepared according to the method for synthesizing intermediate E7, as shown in Table 4.

Table 4 Intermediates E8-E10

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

Step 1: In a 100 mL reaction bottle, dissolve the compound 2-(4-(methylthio)pyrimidin-5-yl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester (384.0 mg, 1.45 mmol) in dichloromethane (40 mL), add m-chloroperbenzoic acid (mCPBA, 3.40 mmol), stir at room temperature for 1.5 h, add sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (5 mL) after the reaction is complete, extract the mixture with ethyl acetate (100 mL×3), combine the organic phases, dry them with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(4-(methylsulfonyl)pyrimidin-5-yl)oxazole-4-carboxylic acid ethyl ester (light yellow solid, 228.0 mg, 63.0%). MS (ESI ⁺ ) m/z＝298.1[M+H] ⁺ .

Step 2: Using 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) as raw materials, 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 according to the method of Step 5 of the synthesis of Intermediate E7. MS (ESI ⁺ ) m/z＝491.2[M+H] ⁺ .

The sixth group of preparation examples: preparation of intermediates F1-F9

Preparation of intermediates F1-F7.

Using commercially available 1-methyl-1H-benzimidazol-5-ol and substituted nitrobenzene compounds as raw materials, intermediates F1-F7 were prepared using the first and second step methods of intermediate A1, as shown in Table 5.

Table 5 Intermediates F1-F7

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

Step 1: Under nitrogen protection, 5-bromo-1,2-difluoro-3-nitrobenzene (2.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (4.3 g, 33.61 mmol) and methylamine hydrochloride (2.8 g, 42.02 mmol) were added in sequence. The temperature was raised to 60 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (70 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 with ethyl acetate/petroleum ether (0-50%) as the eluent to obtain 4-bromo-2-fluoro-N-methyl-6-nitroaniline (yellow solid, 2.0 g, 95.6%). MS (ESI ⁺ ) m/z = 249.0 [M + H] ⁺ .

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), iron powder (4.0 g, 72.28 mmol) and ammonium chloride (3.9 g, 72.28 mmol) were added in sequence, and the mixture was heated to 60°C and stirred for 1 h. After the reaction was completed, 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 with ethyl acetate/petroleum ether (0-100%) as the eluent to obtain 4-bromo-6-fluoro-N ¹ -methyl-1,2-phenylenediamine (brown oil, 1.1 g, 69.5%). MS (ESI ⁺ ) m/z＝219.0[M+H] ⁺ .

Step 3: Under nitrogen protection, dissolve 4-bromo-6-fluoro-N ¹ -methyl-1,2-phenylenediamine (1.1 g, 5.02 mmol) in toluene (20 mL), cool to 0°C, and add p-toluenesulfonamide (86.0 mg, 0.50 mmol) and triethyl orthoformate (1.5 g, 10.04 mmol) in sequence. Heat to 120°C and stir for 16 h. After the reaction is complete, cool to room temperature and add water (50 mL) to the reaction solution. The mixed solution 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 by silica gel column chromatography with ethyl acetate/petroleum ether (0-10%) as the eluent gradient elution to obtain 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] ⁺ .

Step 4: Under nitrogen protection, 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole (1.0 g, 4.37 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (4/1 v/v, 10 mL), and Cu(acac) ₂ (114.3 mg, 0.44 mmol) and BHMPO (143.4 mg, 0.44 mmol) were added in sequence, and then lithium hydroxide monohydrate (769.4 mg, 18.34 mmol) was slowly added. The mixture was heated to 80°C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution, 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 with methanol/dichloromethane (0-20%) as the eluent gradient elution to obtain 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] ⁺ .

Step 5 and step 6: Using 7-fluoro-1-methyl-1H-benzo[d]imidazol-5-ol and 2-chloro-1-fluoro-4-nitrobenzene as raw 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 method of Intermediate A1, Step 1 and Step 2. MS (ESI ⁺ ) m/z = 291.9 [M+H] ⁺ .

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

Step 1: Under nitrogen protection, 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 temperature was raised to 80°C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 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 with ethyl acetate/petroleum ether (0-33%) as the eluent to obtain 7-(2-methyl-4-nitrophenoxy)imidazo[1,2-c]pyrimidine (yellow solid, 180 mg, 20.4%). MS (ESI ⁺ ) m/z＝271.1[M+H] ⁺ .

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), and add iron powder (281.1 mg, 5.03 mmol) and ammonium chloride (269.2 mg, 5.03 mmol) in turn. Heat to 80°C and stir for 2 h. After the reaction is complete, cool to room temperature, concentrate the reaction solution under reduced pressure, and separate the residue by silica gel column chromatography with methanol/dichloromethane (0-18%) as the eluent gradient elution to obtain 4-(imidazo[1,2-c]pyrimidin-7-yloxy)-3-methylaniline (yellow solid, 120 mg, 79.4%). MS (ESI ⁺ ) m/z = 241.0 [M+H] ⁺ .

Preparation Example 7: Preparation of Intermediate G1

Preparation of Intermediate G1 (tert-butyl 1-((4-chloropyrimidin-5-yl)ethynyl)cyclopropyl)carbamate

Dissolve 4-chloro-5-iodopyrimidine (1.0 g, 4.16 mmol) in N,N-dimethylformamide (10 mL), add Pd(PPh ₃ ) ₂ Cl ₂ (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) in sequence, heat to 60°C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (60 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate/petroleum ether (0-50%) as the eluent (yellow solid, 1.2 g, 98.2%). MS (ESI ⁺ ) m/z = 294.1 [M + H] ⁺ .

The eighth group of preparation examples: preparation of final product

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)

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

Under nitrogen protection, 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), and tert-butyl 2-ethynylazetidine-1-carboxylate (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 in sequence, and the temperature was raised to 100 ° C and stirred for 1 h. After cooling to room temperature, water (20 mL) was added to quench the reaction, and the mixed solution was extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography with ethyl acetate/ Petroleum ether = 0-50% was used as the eluent for separation and purification 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] ⁺ .

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

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. Water (20 mL) was added to quench the reaction, and the mixed solution was extracted with ethyl acetate (20 mL×3), and 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] ⁺ .

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

5-(azetidin-2-ylethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (15 mL), triethylamine (59.2 mg, 0.6 mmol) was added, the mixture was cooled to 0°C, acrylic anhydride (22.1 mg, 0.2 mmol) was added dropwise, the mixture was heated to room temperature and stirred for 1 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, 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 high pressure reverse 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-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one.

White solid, MS (ESI ⁺ ) m/z = 465.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.31 (s, 2H), 8.00 (s, 1H), 7.78 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.40-7.29 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 16.8 Hz, 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).

The condensation method in this step also includes: 1) using a commercially available olefin/alkyne 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 olefin/alkyne acid chloride compound as a raw material, triethylamine as a catalyst, THF as a solvent, and reacting at room temperature.

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

The preparation method of the final product 1 is adopted, and the intermediates A1-A28, intermediates B1-B22, intermediates C1-C6 or commercially available alkynyl compounds and other commercially available compounds are used as raw materials to prepare 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.

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

Example 76. (R,Z)-2-Fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide Preparation of 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)

Step 1: (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-carboxylic acid tert-butyl ester

5-(3-aminopropyl-1-ynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (prepared using intermediate A3 as a raw material according to the methods of the first and second steps in Example 1) (120 mg, 0.3 mmol) was dissolved in pyridine (14 mL), and (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 h. Aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography with methanol/dichloromethane = 0-20% as the eluent to give (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 (yellow oil, 70 mg, 35.0%). MS (ESI ⁺ ) m/z = 626.5 [M+H] ⁺ .

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

Dissolve (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-alkynyl-1-yl)amino)-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate (60 mg, 0.09 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (1.2 mL), and stir at room temperature for 1 h. Concentrate under reduced pressure to obtain (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] ⁺ .

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

(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), and formaldehyde aqueous solution (37 wt%, 90 mg, 1.14 mmol) was added. The mixture was stirred at room temperature for 1 h, and sodium triacetoxyborohydride (120.9 mg, 0.5 mmol) was added in batches. The mixture was stirred at room temperature for 4 h. Sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (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 high pressure preparative column (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-benzimidazole -5-yl)oxy)phenyl)amino)pyrimidin-5-yl)propyl-2-yn-1-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide (final product 30A) and (R,E)-2-fluoro-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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 product 30A and the final product 30B specifically corresponded to the cis (Z) configuration or the trans configuration (E).

Final product 30A

Off-white solid, MS (ESI ⁺ ) m/z = 540.2 [M + H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) δ 8.49 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.67 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.16-7.01 (m, 2H), 6.89 (d, J = 8.7 Hz, 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,1H), 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).

Final product 30B

Off-white solid, MS (ESI ⁺ ) m/z = 540.2 [M + H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.31 (s, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.24-7.11 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 5.91-5.83 (m, 1 H),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).

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)

(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 raw material according to the method for synthesizing the final product 30.

White solid, MS (ESI ⁺ ) m/z = 594.2 [M + H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ )δ8.68(s,1H),8.42(s,2H),7.89(s,1H),7.63-7.22(m,4H),7.11-7.0 3(m,1H),6.88(d,J＝8.7Hz,1H),5.91-5.54(m,2H),3.87(s,3H),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).

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)

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

5-((1-aminocyclopropyl)ethynyl)-N-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (prepared using intermediate A2 as a raw material according to the methods of the first and second steps 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, and 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] ⁺ .

Step 2: (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

(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), and morpholine (104.5 mg, 1.2 mmol) and potassium carbonate (331.7 mg, 2.4 mmol) were added in sequence, nitrogen was replaced, 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 a crude product. The crude product was separated and purified by high pressure preparative chromatography (column type: YMC-Actus Triart C18 ExRS, 30×150mm; mobile phase: water (10mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 60mL/min; gradient: 26%-46% acetonitrile 10min; wavelength: 254/220nm) to obtain (2E)-N-(1-((4-((3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)cyclopropyl)-4-morpholinobut-2-enamide.

White solid, MS (ESI ⁺ ) m/z = 564.4 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (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 = 8.7 Hz, 1H), 7.09 (d, J = 2.2 Hz, 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).

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)

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

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), 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. Stir for 1 h. Add water (5 mL) to quench the reaction, extract with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate 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] ⁺ .

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

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) was dissolved in tetrahydrofuran (3 mL), triethylamine trifluoride (171.9 mg, 1.2 mmol) was added, and stirred at room temperature for 1 h. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 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 high pressure preparative 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 for 10 min; wavelength: 254/220 nm) to give 1-(2-((4-((3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)piperidin-1-yl)prop-2-yn-1-one.

Pale yellow solid, MS (ESI ⁺ ) m/z = 491.3 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ )δ8.74(s,1H),8.49(d,J＝13.8Hz,2H),8.17(s,1H),7.56(d,J＝8.7Hz,1 H),7.49(s,1H),7.41-7.32(m,1H),7.08(d,J＝2.3Hz,1H),7.02-6.96(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).

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)

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-butyl alcohol (5 mL), and add tert-butyl (1-((4-chloropyrimidin-5-yl)ethynyl)cyclopropyl)carbamate (Intermediate G1, 201.4 mg, 0.69 mmol), hydrochloric acid and 1,4-dioxane mixture (25.0 mg, 0.69 mmol) in sequence. Heat to 70°C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The pH was adjusted to alkaline with sodium bicarbonate solution. The mixed solution was extracted with ethyl acetate (30 mL×3), and 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 methanol/dichloromethane (0-15%) as eluent to obtain 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 (light yellow solid, 150 mg, 39.9%). MS (ESI ⁺ ) m/z＝549.1[M+H] ⁺ .

Step 2: Dissolve 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) in a mixture of dichloromethane and trifluoroacetic acid (3/1 v/v, 4 mL) and stir at room temperature for 1 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure, the pH is adjusted to alkaline with sodium bicarbonate, the mixture is extracted with ethyl acetate (30 mL×3), the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 5-((1-aminocyclopropyl)ethynyl)-N-(3-chloro-2-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimidin-4-amine (light yellow solid, 200 mg, crude product). MS(ESI ⁺ )m/z=449.2[M+H] ⁺ .

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), and add EDCI (176.8 mg, 0.92mmol) and 2-butynoic acid (19.4mg, 0.23mmol). Stir at room temperature for 0.5h. After the reaction is complete, water (30mL) is added to the reaction solution, the organic phase is separated and dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by high pressure preparative liquid chromatography (column type: Kinetex EVO C18 Column, 21.2×250mm, 5μm; mobile phase: acetonitrile/water (10mmol/L ammonium bicarbonate); flow rate: 60mL/min; gradient: 28-53-11min; wavelength: 254/220nm) 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.

White solid, MS (ESI ⁺ ) m/z = 515.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.75 (dd, J = 9.0, 1.8 Hz, 1H), 3.87 (s, 3H), 1.96 (s, 3H), 1.44-1.34 (m, 2H), 1.19-1.08 (m, 2H).

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

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

Table 7 Final products 145, 150, 151

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)

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

Using intermediate A7 and an alkyne compound as raw 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 synthesis method of Example 1. MS (ESI ⁺ ) m/z = 559.4 [M+H] ⁺ .

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

Under nitrogen protection, 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 mixed solution of ethanol/water (4/1, 5 mL), and 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, and the mixture was heated to 80°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 (20 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 chromatography with methanol/dichloromethane = 0-20% as the eluent to obtain tert-butyl 2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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] ⁺ .

Step 3 and Step 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

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 raw material, 1-(2-((2-amino-4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)ethynyl)pyrrolidine-1-carboxylate was prepared according to the second and third steps of the synthesis method in Example 1.

White solid, MS (ESI ⁺ ) m/z = 494.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42(d,J＝15.4Hz,1H),8.23(s,2H),7.65(d,J＝8.5Hz,1H),7.37(s,1H), 7.31-7.22(m,1H),7.10(d,J＝8.9Hz,1H),6.89-6.81(m,2H),6.25(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).

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)

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

Under nitrogen protection, methyl 2-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-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, and the mixed solution was extracted with dichloromethane/methanol (10/1, 30 mL×3). The combined organic phase was washed with a saturated sodium chloride solution (30 mL×3), and the combined organic phase was 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] ⁺ .

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

Under nitrogen protection, (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) were added to a 40 mL single-mouth bottle in sequence, and the temperature was raised to 90 ° C and stirred for 24 h. After cooling to room temperature, water (20 mL) was added at 0 ° C to quench the reaction, and it was extracted with dichloromethane/methanol (10/1; 30 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate with a saturated sodium chloride solution (30 mL×3), and 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 with methanol/dichloromethane = 10% as the eluent to obtain 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] ⁺ .

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

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), triphenylphosphine (34.7 mg, 0.14 mmol) and water (0.1 mg, 0.007 mmol) were added, and 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 obtain 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] ⁺ .

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

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 third step of Example 1.

White solid, MS (ESI ⁺ ) m/z = 482.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ )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).

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

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.

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

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)

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

(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 a saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction. 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] ⁺ .

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

Under nitrogen protection, (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)formaldehyde (374.0 mg, 0.87 mmol) and dry tetrahydrofuran (20 mL) were added to a 40 mL reaction bottle, 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 mixed solution was concentrated under reduced pressure. The residue was purified by silica gel column using methanol/dichloromethane = 0%-20% as eluent to obtain (2-(4-((3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethanol (light yellow solid, 284.0 mg, 73%). MS (ESI ⁺ ) m/z = 443 [M+H] ⁺ .

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

Using (2-(4-((3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazol-4-yl)ethanol as raw material, 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 according to the second, third and fourth steps of the final product 81.

White solid, MS (ESI ⁺ ) m/z = 496.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.70-7.60 (m, 2H), 7.57 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 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),5.69-5. 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).

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)

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 completed, 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 residue was separated by silica gel column chromatography using methanol/dichloromethane (10%) as eluent to obtain 2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxazole-4-carboxaldehyde (yellow oil, 250 mg, 66.1%). MS (ESI ⁺ ) m/z＝427.1[M+H] ⁺ .

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, tert-butylsulfenamide (85.3 mg, 0.70 mmol) and tetraethyl titanate (267.5 mg, 1.17 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. After the reaction was completed, a 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. The residue was separated by silica gel column chromatography using methanol/dichloromethane (10%) as an eluent 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] ⁺ .

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, (1,3-dioxane-2-ethyl)magnesium bromide (621.3 mg, 2.83 mmol) was added dropwise, and 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. After the mixture was cooled to room temperature, it 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 residue was separated by reverse phase C18 chromatography with acetonitrile/water (10%-50%-20 min) as the eluent and gradient elution to give N-(3-(1,3-dioxane-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-sulfinamide (white solid, 20 mg, 10.9%). MS (ESI ⁺ ) m/z＝646.3[M+H] ⁺ .

Step 4: At 0°C, N-(3-(1,3-dioxane-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-sulfinamide (20.0 mg, 0.031 mmol) was dissolved in a mixture of trifluoroacetic acid and water (1/1 v/v, 1 mL) and stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give 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 (yellow oil, 15 mg, crude product). MS(ESI ⁺ )m/z=466.3[M+H] ⁺ .

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, add sodium triacetoxyborohydride (13.7 mg, 0.064 mmol), return to room temperature and stir for 1 h. After the reaction was complete, saturated sodium bicarbonate aqueous 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 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] ⁺ .

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 completed, water (10 mL) was added to the reaction solution, 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 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%).

White solid, MS (ESI ⁺ ) m/z = 522.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 0.5H), 10.60 (s, 0.5H), 8.94 (d, J = 3.8 Hz, 1H), 8.73 (s, 1H), 8.37-8.10 (m, 2H), 7.78-7.47 (m, 3H), 7.16-7.09 (m, 1H), 7.00 (dd, J = 8.7, 2.3 Hz, 1H), 6.89 (dd, J = 8.7, 2.0 Hz, 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).

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)

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

Step 2: Dissolve 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) in N,N-dimethylformamide (5 mL), add DIEA (420.9 mg, 3.26 mmol) and HATU (1.2 g, 3.26 mmol) in turn, and stir at room temperature for 5 min. Then add (3-amino-1-Boc-3-piperidinyl)methanol (500.0 mg, 2.17 mmol) and stir at room temperature for 3 h. After the reaction was complete, water (5 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 a saturated sodium chloride solution (5 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol/dichloromethane (0-15%) as the eluent gradient elution to obtain 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] ⁺

Step 3: Under nitrogen protection, 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). Warm to room temperature and stir for 1 h. After the reaction was completed, sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, the mixed solution was extracted with dichloromethane (10 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by basic silica gel column chromatography with methanol/dichloromethane (0-8%) as the eluent gradient elution to obtain 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-carboxylic acid tert-butyl ester (white solid, 200 mg, 43.9%). MS (ESI ⁺ ) m/z＝570.4[M+H] ⁺ .

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 obtain 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 (brown oil, 200 mg, crude product). MS(ESI ⁺ )m/z=470.4[M+H] ⁺ .

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 the reaction was completed, 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 obtain 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%).

White solid, MS (ESI ⁺ ) m/z = 524.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

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)

Step 1: tert-butyl (3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)carbamate

5-((4-((5-iodopyrimidin-4-yl)amino)-2-methylphenyl)oxy)-1-methylbenzimidazole (Intermediate A2, 300 mg, 0.7 mmol), 1,4-dioxane/water mixture (5/1, 3 mL), 3-((tert-butoxycarbonyl)amino)phenylboronic acid (233.3 mg, 1 mmol), Pd(PPh ₃ ) ₄ (75.8 mg, 0.07 mmol) and potassium carbonate (272 mg, 2.0 mmol) were added to a 25 mL reaction bottle in sequence, nitrogen was replaced, the temperature was raised to 90°C and stirred for 1 h. After cooling to room temperature, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and 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 chromatography with 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] ⁺ .

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

Using tert-butyl (3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)carbamate as raw material, N-(3-(4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)phenyl)acrylamide was prepared according to the synthesis method of the second and third steps of Example 1.

White solid, MS (ESI ⁺ ) m/z = 477.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.16 (d, J = 2.1 Hz, 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).

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)

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

White solid, MS (ESI+) m/z = 492.1 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ )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＝2.3Hz,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).

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)

Under nitrogen protection, 5-bromo-6-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-4-amine (Intermediate A10, 200 mg, 0.5 mmol), 1,4-dioxane/water mixture (10/1, 5.5 mL), 3-(prop-2-enylamino)phenylboronic acid (134.7 mg, 0.7 mmol), Pd(dppf)Cl ₂ (34.4 mg, 0.05 mmol) and cesium carbonate (459.7 mg, 1.4 mmol) were added to a 25 mL single-mouth bottle in sequence, and 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×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 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.

White solid, MS (ESI ⁺ ) m/z = 492.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.25 (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).

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)

Using intermediate A12 and 3-((tert-butoxycarbonyl)amino)phenylboronic acid as raw materials, 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 according to the method for preparing final product 110.

White solid, MS (ESI+) m/z = 550.1 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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),6.7 3(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).

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)

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

Under nitrogen protection, 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), and 2,6-diazaspiro[3.3]heptane-2 Tert-butyl formate (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), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl gold (I) chloride (XPhosAuCl, 84 mg, 0.16 mmol), heated to 90 ° C and stirred for 1 h. Cooled to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, 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 chromatography with ethyl acetate/petroleum ether (0-50%) as the eluent by gradient elution 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] ⁺ .

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]heptane-2-yl)prop-2-en-1-one

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 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.

White solid, MS (ESI+) m/z = 482.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J = 16.5 Hz, 2H), 8.05 (s, 1H), 7.76 (s, 1H), 7.62-7.45 (m, 3H), 7.03 (d, J = 2.2 Hz, 1H), 7.00-6.92 (m, 1H), 6.82 (d, J = 8.7 Hz, 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).

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

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

White solid, MS (ESI+) m/z = 524.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.40-8.30 (m, 2H), 8.20-7.99 (m, 3H), 7.60-7.41 (m, 3H), 6.98 (s, 1H), 6.91 (d, J = 1.8 Hz, 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).

Example 105. Preparation of N-methyl-N-(2-(4-(3-methyl-4-(1-toluene imidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl acrylamide (final product 115)

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

Under nitrogen protection, 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), and 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 Cs ₂ CO ₃ (531 mg, 1.6 mmol) were added in sequence, and the temperature was raised 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 organic phases were combined and 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 chromatography with 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] ⁺ .

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

Under nitrogen protection, 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), and 4 M salt was added dropwise. A solution of 1,4-dioxane (0.2 mL) of the acid was stirred at room temperature for 2 h. After the reaction was completed, sodium bicarbonate solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and 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 chromatography with 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] ⁺ .

Step 3: N-methyl-N-(2-(4-(3-methyl-4-(1-toluene imidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl acrylamide

Using N-(3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)-5-(2-methylaminoethoxy)pyrimidin-4-amine and acrylic anhydride as raw materials, N-methyl-N-(2-(4-(3-methyl-4-(1-tolueneimidazole-5-oxy)phenyl)amino)pyrimidin-5-yl)oxy)ethyl acrylamide was prepared according to the third step of the synthesis method in Example 1.

White solid, MS (ESI+) m/z = 459.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52-8.03 (m, 4H), 7.75 (d, J = 2.8 Hz, 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 = 2.8 Hz, 3H).

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

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

Table 9 Final products 117 and 118

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)

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

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), 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, and stirred at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were backwashed three times with water (10 mL), and 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 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%).

Step 2 and Step 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

Using tert-butyl 2-(((4-((3-methyl-4-((1-methylbenzimidazol-5-yl)oxy)phenyl)amino)pyrimidin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate as 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 synthesis method of the second and third steps of Example 1.

White solid, MS (ESI+) m/z = 493.1 [M + H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD)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),4.33-4 .11(m,2H),3.91(s,3H),3.84-3.60(m,2H),2.28(s,3H),2.21-2.00(m,5H).

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)

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

White solid, MS (ESI+) m/z = 485.4 [M + H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ )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),6.4 1-6.31(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).

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)

Step 1: Using 5-((1-aminocyclopropyl)ethynyl)-N-(3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)pyrimidin-4-amine and 3-(1-(tert-butyloxycarbonyl)pyrrolidin-2-yl)propiolic acid (intermediate C4) as raw materials, 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 according to the method of step 3 of synthesizing final product 58. MS (ESI ⁺ ) m/z=632.3[M+H] ⁺ .

Step 2: Using 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 as raw material, 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 (yellow solid, 150 mg, crude) was prepared according to the method of the second step of the synthesis of the final product 1. MS (ESI ⁺ ) m/z=532.3[M+H] ⁺ .

Step 3: Under nitrogen protection, 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)propiolamide (140.0 mg, 0.26 mmol) was dissolved in methanol (3 mL), cooled to 0 °C, and formaldehyde aqueous solution (11.9 mg, 0.40 mmol) was slowly added dropwise, and then cyanoborohydride was added. Sodium (82.7 mg, 1.32 mmol). Warm to room temperature and stir for 1 h. After the reaction is complete, water (30 mL) is added to the reaction solution, the mixed solution is extracted with ethyl acetate (30 mL×3), the organic phases are combined and dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is 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.

White solid, MS (ESI ⁺ ) m/z = 546.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.48 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.7, 2.7 Hz, 2H), 7.08 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 8.7, 2.3 Hz, 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).

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)

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 NaBH ₃ CN (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, the mixed solution 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 obtain 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] ⁺ .

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 raw 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.

White solid, MS (ESI ⁺ ) m/z = 496.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.96(s,0.5H),10.65(s,0.5H),8.95(d,J＝3.5Hz,1H),8.73(s,1H) ,8.35(s,0.5H),8.28(s,0.5H),8.17(s,1H),7.70-7.50(m,3H),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).

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)

Step 1, step 2, step 3: Using 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 (Intermediate E6) as starting material, 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 (yellow solid, 95 mg, 77.2%) was prepared according to the method of step 1, step 2, step 3 of final product 81. MS (ESI ⁺ ) m/z＝564.3[M+H] ⁺ .

Step 4: Dissolve 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) in a mixture of trifluoroacetic acid/water (9/1 v/v, 3 mL) and stir 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, 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 give 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 (yellow solid, 62 mg, 83.0%). MS (ESI ⁺ ) m/z=443.3[M+H] ⁺ .

Step 5: Using 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 as raw material, prepare 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 according to the method of step 4 of final product 81.

White solid, MS (ESI ⁺ ) m/z = 497.1 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ )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＝8.7,2.3 Hz,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).

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)

1-(4-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid was prepared according to the method for synthesizing the final product 108.

White solid, MS (ESI ⁺ ) m/z = 510.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.73 (d, J = 4.9 Hz, 2H), 8.23-8.16 (m, 1H), 7.60-7.49 (m, 3H), 7.08 (d, J = 2.1 Hz, 1H), 7.01-6.93 (m, 1H), 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).

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)

Step 1: Using intermediate A25 and (3-amino-1-Boc-3-piperidinyl)methanol as raw 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 (light 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] ⁺ .

Step 2: 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 raw materials, 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 (light yellow oil, 370 mg, 71.4%) was prepared according to the method of the second step of the synthetic intermediate E6. MS (ESI ⁺ ) m/z＝723.5[M+H] ⁺ .

Step 3: Using 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 as starting material, tert-butyl 2-(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 was prepared according to the method of step 3 of the synthesis of final product 108 (light yellow oil, 180 mg, 49.9%). MS (ESI ⁺ ) m/z=705.5[M+H] ⁺ .

Step 4: In a 40 mL sample bottle, dissolve 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) in a mixture of trifluoroacetic acid and water (4.4 mL, 1/10 v/v), heat to 80 °C and stir 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] ⁺ .

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.

White solid, MS (ESI ⁺ ) m/z = 539.4 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.48 (d, J = 47.1 Hz, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.55 (d, J = 8.8 Hz, 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,1 H),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).

Comparative Compound A

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

MS(ESI ⁺ )m/z＝403.1[M+H] ⁺ . ¹ H NMR (300MHz, DMSO-d ₆ )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). ¹⁹ F NMR (282MHz, DMSO-d ₆ )δ-115.570,-116.095.

Experimental Example 1 Cell proliferation inhibition experiment

The CellTiter-Glo ^™ live cell detection kit uses luciferase as a detection substance. Luciferase requires the participation of ATP in the luminescence process. Add CellTiter-Glo ^™ reagent to the cell culture medium and measure the luminescence value. The light signal is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of live cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the proliferation of cells can be detected.

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

1. Experimental Design

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

2. Reagents and Consumables

3. Experimental Procedure

3.1 Cell culture

a) All cells were cultured according to the method recommended by ATCC. Cells in the logarithmic growth phase were harvested. Cell viability was tested to ensure that the cell viability was above 90%.

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.

c) Cell culture environment: cultured at 37°C, 5% CO ₂ , and 95% humidity.

3.2 Drug dilution

a) Drug storage solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.

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

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

3.3 Dosing

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

b) Prepare positive control drug and DMSO blank control.

c) Add 5 μL 20X drug solution or 10 μL 10X drug to each well of a 96-well plate seeded with cells, and set up 2 replicate wells for each drug concentration.

d) The cells in the 96-well plate to which the drugs had been added were cultured for a further 72 hours at 37°C, 5% CO ₂ , and 95% humidity, and then subjected to CTG analysis.

3.4 Endpoint plate reading

a) Melt the CTG reagent, add 50 μL of CTG solution to each well and shake well.

b) Place the cell plate at room temperature for 10 minutes to stabilize the luminescent signal.

c) Read the fluorescence value using an enzyme reader.

4. Data Processing

The data were analyzed using GraphPad Prism 7.0 software, and the dose-effect curves were fitted using nonlinear S-curve regression, from which the _IC50 values were calculated.
Inhibition rate (Inh%) = 100-(RLU _compound -RLU _blank )/(RLU _control -RLU _blank )*100%.

5. Experimental results

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

Table 10. Inhibitory activity of compounds on proliferation of HER2 775_776insYVMA Ba/F3 cell line and SK-BR-3 cell line (IC ₅₀ , nM)

As can be seen from the table, the compounds of the present invention have good proliferation inhibition activity on 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 reaches nanomolar concentration.

Example 2: A431 phosphorylation experiment

Cell culture

a) All cells were cultured according to the method recommended by ATCC. Cells in the logarithmic growth phase were harvested. Cell viability was tested to ensure that the cell viability was above 90%.

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

c) Remove the culture medium, add 25 μL HBSS to the 384-well plate, and leave overnight.

3.2 Drug dilution

a) Drug storage solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO storage solution.

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

3.3 Dosing

a) All drugs were diluted 3-fold starting from 10 mM concentration, with 10 concentration gradients.

b) The cells in the 384-well plate to which the drug had been added were placed under conditions of 37°C, 5% CO ₂ , and 95% humidity and cultured for a further 30 minutes.

3.4 Detection

a) Add EGF as an activator and stimulate for 15 min.

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

c) AlphaScreen is read by Envision.

4. Data Processing

The data were analyzed using GraphPad Prism 8.0 software, and the dose-effect curves were fitted using nonlinear S-curve regression, from which the _IC50 values were calculated.
Inhibition rate (Inh%) = 100-(Signal _compound -Signal _{Ave_PC} )/(Signal _{Ave_VC} -Signal _{Ave_PC} )*100%.

Signal _{Ave_PC} : Average signal value of the positive control on the entire plate

Signal _{Ave_VC} : The average signal of the negative control of the entire plate

Table 11. Compounds inhibit EGFR phosphorylation of pEGFR in A431 cell line (IC ₅₀ nM)

As can be seen from the table, the IC ₅₀ value of the compounds of the present invention for inhibiting EGFR phosphorylation in A431 cell line is >1 μM, indicating that the compounds of the present invention have a weaker inhibition on wild-type EGFR and have good selectivity for wild-type EGFR.

Example 3: P-gp substrate evaluation experiment

1. Experimental Design

Cell culture

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.

2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks. The incubator was set at 37°C, 5% CO ₂ , and relative humidity was maintained at 95%. When the cell confluence reached 70-90%, it could be used to inoculate Transwell.

3) Before cell inoculation, add 50 μL of cell culture medium to each well of the upper chamber of the Transwell and 25 mL of cell culture medium to the lower culture plate. Place the culture plate in a 37°C, 5% CO ₂ incubator for 1 hour before inoculating cells.

4) Gently wash the cells with 5 mL PBS. Discard the PBS, add 1.5 mL pancreatin containing EDTA, and incubate at 37°C for 5 to 10 minutes until the cells are completely detached. Add serum-containing medium to terminate the digestion.

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

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

MDCKII-MDR1 cell seeding

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

1.45×10 ⁵ cells/cm ² .

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

Assessment of cell monolayer integrity

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

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

3) After the measurement, place the Transwell culture plate back into the incubator.

4) Calculation of resistance value:

Measured resistance value (ohms) x membrane area (cm ² ) = TEER value (ohm·cm ² )

If the TEER value is <42 ohms·cm ² , the hole cannot be used for penetration testing.

Drug penetration test

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

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

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

4) Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

5) After incubation, take 50 μL of samples from each well of the upper and lower chambers of the Transwell culture plate and add them to new sample tubes. Add 4 times the volume of acetonitrile containing internal standards (200nM alprazolam, 200nM labetalol, 200nM diclofenac, 100nM tolbutamide) to the sample tubes, vortex for 5 minutes, and centrifuge at 3,220g for 15 minutes. Pipette 100 μL of the supernatant and dilute with an equal volume of water for LC-MS/MS analysis. All samples were prepared in triplicate.

6) Use the leakage of fluorescent yellow to evaluate the integrity of the cell monolayer membrane after 2 hours of incubation. Use HBSS (10mM HEPES, pH 7.4) to dilute the fluorescent yellow stock solution to a final concentration of 100μM. Add 100μL of fluorescent yellow solution to each well of the upper Transwell insert plate, and add 300μL of HBSS (10mM HEPES, pH 7.4) to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, aspirate 80μL of solution from the upper and lower layers of each well into a new 96-well plate. Use a microplate reader to perform fluorescence measurement under the conditions of excitation wavelength 485nm and emission wavelength 530nm.

2. Data processing

Data calculations were performed using Excel, and the apparent permeability coefficient (P _app , unit: cm/s) of the compound was calculated using the following formula:

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

Table 12. Efflux rates of the tested compounds

Example 4: Cassette pharmacokinetic test of compounds in mice

Experimental purpose: Using ICR mice as test subjects, the LC/MS/MS method was used to determine the compound administered by oral gavage (PO), and the drug concentration of the compound in plasma was detected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h, to study the pharmacokinetic behavior of the compound of the present invention in mice and evaluate its pharmacokinetic characteristics.

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

Table 13. Pharmacokinetic test results of cassette in mice

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

The above embodiments are only used to help understand the method and core idea of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims (11)

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:
Wherein, 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 alkylthiol, _3-12 -membered cycloalkylthiol, 3-12-membered heterocyclylthiol, 3-12-membered cycloalkyl-C _1-6 alkylene-thiol or 3-12-membered heterocyclyl-C _1-6 alkylene-thiol, wherein the C 1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclylthiol, 3-12-membered cycloalkyl-C _1-6 alkylene-thiol or 3-12-membered heterocyclyl-C _1-6 alkylene-thiol _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 alkylthiol, 3-12 membered cycloalkylthiol, _3-12 membered heterocyclylthiol, 3-12 membered cycloalkyl-C _1-6 alkylene-thiol and 3-12 membered heterocyclyl-C _1-6 alkylene-thiol are optionally substituted with one or more R′; Y ¹ is a chemical bond, CR ⁵ R ⁶ , a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R′; Y ² is a chemical bond, a 3-12 membered heterocyclic group or NR ⁷ , wherein the 3-12 membered heterocyclic group is optionally substituted by one or more R′; Z is C(═O) or S(O) ₂ ; L ₁ is NR ⁸ , O, CR ⁵ R ⁶ , S, S(O) or S(O) ₂ ; L ₂ 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 ^Re ; 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; ^X1 is a chemical bond, N, CH, _CH2 , O, S, S(O) or S(O) ₂ ; ^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ; ^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time; X ⁵ is a chemical bond, N, CH, CH ₂ , O, S, S(O) or S(O) ₂ ; X ⁶ is N, O, S, C(=O), S(O), S(O) ₂ , N(=O), N(O) ₂ , N ⁺ -O ^- or CH; ^R1 is a halomethyl group, a _C2-4 alkenyl group, a _C2-4 alkynyl group, an oxetane group or a _C4-6 cycloalkenyl group, wherein the _C2-4 alkenyl group, the _C2-4 alkynyl group, the oxetane group and the _C4-6 cycloalkenyl group are optionally substituted with one or more halogen, cyano, _C1-4 alkyl group, a halo-substituted _C1-4 alkyl group, a 3-12-membered cycloalkyl group, a deuterium atom, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, a 6-12-membered aryl group, a _C1-3 alkoxy- _C1-3 alkyl group, or ^NRaRb , wherein the _C1-4 alkyl group, the halo-substituted _C1-4 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 5-12-membered heteroaryl group, ^the 6-12-membered aryl group and the _C1-3 alkoxy- _C1-3 alkyl group are optionally substituted with one or more R′; ^R2 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a _hydroxyl group, an amino group, a _C1-6 alkyl group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the _C2-4 alkenyl group, the _C2-4 alkynyl group, the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group are optionally substituted by one or more R's; ^R3 is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, _{a C1-6} alkyl group, a _{halogenated C1-6} alkyl group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a _3-12 -membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _{3-12-membered heterocyclyloxy group, RcRdN-C1-6} ^{alkylene -} oxy group, a 3-12-membered cycloalkyl- _C1-6 alkylene-oxy group, a _3-12 -membered heterocyclyl-C1-6 alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, C(=O) ^NRc , ^NRcC (=O) ^Rd or ^NRcC (=O) ^NRd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated C1-6 alkyl group, the C2-4 alkenyl group, the _C2-4 alkynyl group C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^c R ^d N c _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 alkylthio, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′; ^R4 is a hydrogen atom, a halogen, a cyano group, an amino group, a _C1-6 alkyl group, a _C2-4 alkenyl group, a _C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a 3-12-membered heterocyclyloxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group or a di( _C1-6 alkyl)amino group, wherein the amino group, the _C1-6 alkyl group, the _C2-4 alkenyl group, the _C2-4 alkynyl group, the 3-12-membered cycloalkyl group, the _3-12- membered heterocyclyl group, the C1-6 alkoxy group, the 3-12-membered cycloalkyloxy group, the 3-12-membered heterocyclyloxy group, the C1-6 alkylthiol group, the C1-6 alkylamino group or the di(C1-6 alkyl)amino group Alkyl, 3-12 membered heterocyclyl, 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 are optionally substituted with one or more R′; ^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-6 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 5-12-membered heteroaryl group, _{a 6-10-} membered aryl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12 -membered heterocyclyloxy group, a _C1-6 alkylmercapto group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, a cyano- _C1-6 alkyl-, a _{C1-6 alkoxy-C1-6} alkyl-, a 3-12-membered cycloalkyl- _C1-6 alkyl-, or a 3-12-membered heterocyclyl- _C1-6 alkyl-; the hydroxyl, amino group, _C1-6 alkyl group, a halogenated _C1-6 alkyl group, a C2-4 alkenyl group, a _C2-4 alkynyl group _2-4- alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, 5-12-membered heteroaryl, 6-10-membered aryl, C _1-6 alkoxy, halo-C _1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, C _{1-6 alkylthiol, 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- are optionally substituted with one or more R′; or R ⁵ together with R ⁶ and the C atom to which they are attached form 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′; ^R7 is a hydrogen atom, a _C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a _C1-6 haloalkyl group, a 5-12-membered heteroaryl group or a 6-12-membered aryl group, wherein the _C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the _C1-6 haloalkyl group, the 5-12-membered heteroaryl group and the 6-12-membered aryl group are optionally substituted by one or more R's; R ⁸ is a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a cyano-C _1-6 alkyl group or a hydroxy C _1-6 alkyl group; ^Ra and ^Rb are each independently a hydrogen atom, a _C1-4 alkyl group, a _C1-4 haloalkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl- _C1-4 alkyl group, a 3-12-membered heterocyclyl group, a _3-12 -membered cycloalkyl- _C1-4 alkyl group, a 3-12-membered heterocyclyl group- _C1-4 alkyl group, a _C1-4 alkoxy- _C1-4 alkyl group, or a deuterated C1-4 alkyl group, wherein the _C1-4 alkyl group, the C1-4 haloalkyl group, _{the 3-12} -membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl-C1-4 alkyl group, the 3-12-membered heterocyclyl group- _C1-4 alkyl group, the _C1-4 alkoxy- _C1-4 alkyl group and the deuterated _C1-4 alkyl group are optionally substituted by one or more R′; or ^Ra , ^Rb and the N atom to which they are attached together form a 3-12 membered heterocyclic group, which is optionally substituted by one or more R'; R ^c and R ^d are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclyl group, a 3-12-membered cycloalkyl group-C _1-6 alkyl group, or a 3-12-membered heterocyclyl group-C _1-6 alkyl group, wherein the C _1-6 alkyl group, the C _2-4 alkenyl group, the C _2-4 alkynyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclyl group, the 3-12-membered cycloalkyl group-C _1-6 alkyl group, and the 3-12-membered heterocyclyl group-C _1-6 alkyl group are optionally substituted with one or more R′; R ^e is a deuterium atom, a halogen, a cyano group, a nitro group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _2-6 heteroalkenyl group, a 3-12-membered saturated or unsaturated cycloalkyl group, a 3-12-membered saturated or unsaturated heterocyclic group, a halogenated C _1-6 alkyl group, a halogenated C _1-6 alkoxy group, OR ^e1 , SR ^e1 , SOR ^e1 , SO ₂ R ^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 , SO ₂ NR ^e1 , NHS(O) ₂ R ^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 C _1-6 haloalkyl and C _1-6 haloalkoxy are optionally substituted by one or more R′; ^Re1 and ^Re2 are each independently a hydrogen atom, a deuterium atom, a _C1-4 alkyl group, a halogenated _C1-4 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, or ^Re1 and ^Re2 together with the connected N atom form a 3-12-membered heterocyclic group; R′ is each independently a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C _1-6 alkyl group, _{a C 2-6 alkenyl} group, a C _2-6 alkynyl group, a halogenated C _1-4 alkyl group, a deuterated C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group, a C _1-4 alkylamino group, a di(C _1-4 alkyl)amino group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkyl group, a halogenated C _1-6 alkoxy group or an oxo group (═O). The nitrogen-containing heteroaromatic ring compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, wherein, in Formula I, M is N or CR ³ ; ^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-4 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a _3-12- membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12- membered heterocyclyloxy group, ^RcRdN - ^C1-6 alkylene-oxy group, a 3-12-membered cycloalkyl- _C1-6 alkylene-oxy group, a 3-12-membered heterocyclyl- _C1-6 alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, C(=O) ^NRc , ^NRcC (=O) ^Rd or ^NRcC (=O) ^NRd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated C1-6 alkyl group, the _C2-4 alkenyl group, the C2-4 alkynyl group C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^c R ^d N c _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 alkylthio, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′; R ^c and R ^d are each independently 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 ; ^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a _{halogenated C1-4} alkyl group, a _C1-6 alkoxy group, a halogenated _C1-6 alkoxy group, a 3-12-membered heterocyclyloxy group, a ^{RcRdN -} C1-6alkylene-oxy group, _{a 3-12} -membered heterocyclyl-C1-6alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group or ^NRcC (=O) ^Rd , wherein the hydroxyl group, the 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 N-C _1-6 alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, C _{1-6 alkylthiol, C 1-6 alkylamino} and NR ^c C(═O)R ^d are 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 ; ^R3 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. The nitrogen-containing heteroaromatic ring compound or the pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate according to claim 1 or 2, wherein, in Formula I, X is N or CR ⁴ ; ^R4 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 ; ^R4 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; R′ is a deuterium atom, F, Cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy; Preferably, in formula I: A is _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy or 3-12-membered heterocyclyl- _C1-6 alkylene-oxy, and the _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy and 3-12-membered heterocyclyl- _C1-6 alkylene-oxy are 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. 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 is a chemical bond, CR ⁵ R ⁶ , a 3-12-membered cycloalkyl group or a 3-12-membered heterocyclic group, and the 3-12-membered cycloalkyl group and the 3-12-membered heterocyclic group 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; ^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, a 5-12-membered heteroaryl group, a _6-10 -membered aryl group, a cyano- _C1-6 alkyl group, a C1-6 alkoxy- _C1-6 alkyl group, a _C1-6 alkylamino group or a 3-12-membered cycloalkyl- _C1-6 alkyl group; the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-6 alkyl group, the 3-12-membered cycloalkyl group, the 3-12-membered heterocyclic group, the 5-12-membered heteroaryl group, the 6-10-membered aryl group, the cyano- _C1-6 alkyl group, the _{C1-6 alkoxy-C1-6 alkyl} group, the _C1-6 alkylamino group and the 3-12-membered cycloalkyl-C1-6 _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 they are attached form 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 with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; Preferably, in Formula I, Y ¹ is a chemical bond, CR ⁵ R ⁶ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, and 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 are each independently 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 they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl or oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxetanyl and oxetanyl are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy. 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 , and 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 , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group; 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, L ₁ 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 hydroxy C _1-6 ethyl group; Preferably, in Formula I, L ₁ 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). 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 a 5-6-membered heteroaryl group, and the phenyl and 5-6-membered heteroaryl groups are optionally substituted by one or more ^Re ; 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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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 ^Re ; 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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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, CH ₂ , S, O, S(O) or S(O) ₂ ; ^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ; ^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time; X ⁵ is a chemical bond, N, CH, CH ₂ , O or S; ^X6 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:
The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, 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, epoxypropanyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, and the halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, epoxypropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl are optionally replaced by one or more F, Cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, epoxypropanyl, epoxybutanyl, deuterium atom, phenyl, pyridinyl or NR ^a R ^b is substituted, wherein 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 are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl or acridinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl and acridinylethyl are optionally substituted with one or more R ′; or ^Ra, together with ^Rb and the N atom to which they are 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 is selected from the following groups:
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 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a C _1-4 alkyl group or a 3-6 membered cycloalkyl group; 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 ; ^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogenated _{C1-4 alkyl} group, a _C2-4 alkenyl group, a C2-4 alkynyl group, a 3-12-membered cycloalkyl group, a _3-12- membered heterocyclyl group, a _C1-6 alkoxy group, a halogenated C1-6 alkoxy group, a 3-12-membered cycloalkyloxy group, a _3-12- membered heterocyclyloxy group, ^RcRdN - ^C1-6 alkylene-oxy group, a 3-12-membered cycloalkyl- _C1-6 alkylene-oxy group, a 3-12-membered heterocyclyl- _C1-6 alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group, a di( _C1-6 alkyl)amino group, C(=O) ^NRc , ^NRcC (=O) ^Rd or ^NRcC (=O) ^NRd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated C1-6 alkyl group, the _C2-4 alkenyl group, the C2-4 alkynyl group C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^c R ^d N c _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 alkylthio, C _1-6 alkylamino and di(C _1-6 alkyl)amino are optionally substituted with one or more R′; R ^c and R ^d are each independently 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 ; ^R4 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 _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy, or 3-12-membered heterocyclyl- _C1-6 alkylene-oxy, wherein the _C2-4 alkenyl, _C2-4 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, _C1-6 alkoxy, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyloxy, 3-12-membered cycloalkyl- _C1-6 alkylene-oxy, and 3-12-membered heterocyclyl- _C1-6 alkylene-oxy are optionally substituted with one or more R′; Y ¹ is a chemical bond, CR ⁵ R ⁶ , a 3-12 membered cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the 3-12 membered cycloalkyl group and the 3-12 membered heterocyclyl group 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; ^R5 and ^R6 are each independently a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amino group, _{a C1-6} alkyl group, a halogenated C1-6 alkyl group, a 3-12-membered cycloalkyl group, a 3-12-membered heterocyclic group, a 5-12-membered heteroaryl group, a _6-10- membered aryl group, a cyano- _C1-6 alkyl group, a _C1-6 alkoxy- _C1-6 alkyl group, a _C1-6 alkylamino group or a 3-12-membered cycloalkyl- _C1-6 alkyl group; substituted 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- are optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups; Y ² is a chemical bond, a 3-12 membered heterocyclic group or NR ⁷ , wherein 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 ; L ₁ 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 hydroxy C _1-6 ethyl group; _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 ^Re ; 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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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, CH ₂ , S, O, S(O) or S(O) ₂ ; ^X2 is N, CH, _CH2 , O, S, S(O) or S(O) ₂ ; ^X3 and ^X4 are each independently N or C, and ^X3 and ^X4 are not N at the same time, and ^X1 , ^X2 and ^X3 are not N at the same time; X ⁵ is a chemical bond, N, CH, CH ₂ , O or S; ^X6 is N, O, S or CH; or R ¹ is a halomethyl group, a vinyl group, a propenyl group, a ethynyl group, a propynyl group, a butynyl group, a glycidyl group, a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group, wherein the halomethyl group, the vinyl group, the propenyl group, the ethynyl group, the propynyl group, the butynyl group, the glycidyl group, the cyclobutenyl group, the cyclopentenyl group or the cyclohexenyl group are optionally substituted with one or more F, Cl, a methyl group, an ethyl group, a cyclopropyl group, an acridinyl group, a pyrrolidinyl group, a piperidinyl group, a glycidyl group, a butylene oxide group, a deuterium atom, a phenyl group, a pyridinyl group or a NR ^a R ^b group, wherein the methyl group, the ethyl group, the cyclopropyl group, the acridinyl group, the pyrrolidinyl group, the piperidinyl group, the glycidyl group, the butylene oxide group, the phenyl group or the pyridinyl group are optionally substituted with one or more R ′; R ^a and R ^b are each independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl or acridinylethyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl and acridinylethyl are optionally substituted with one or more R ′; or ^Ra, together with ^Rb and the N atom to which they are 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); ^R2 is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, an amino group, a _C1-4 alkyl group or a 3-6 membered cycloalkyl group; Preferably, in Formula I: M is N or CR ³ ; ^R3 is a hydrogen atom, a deuterium atom, F, Cl, Br, a cyano group, a hydroxyl group, an amino group, _{a C1-6 alkyl} group, a halogenated _C1-4 alkyl group, a _C1-6 alkoxy group, a halogenated ^C1-6 alkoxy group, a 3-12-membered _{heterocyclyloxy} group, a ^{RcRdNC1-6alkylene} -oxy group, _{a 3-12} -membered heterocyclyl-C1-6alkylene-oxy group, a _C1-6 alkylthiol group, a _C1-6 alkylamino group or ^NRcC (=O) ^Rd , wherein the hydroxyl group, the amino group, the _C1-6 alkyl group, the halogenated _C1-4 alkyl group, the _C1-6 alkoxy group, the halogenated _C1-6 alkoxy group, the 3-12-membered heterocyclyloxy _group , ^{the RcRdNC1-6} Alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, C _1-6 alkylthiol, C _1-6 alkylamino and NR ^c C(═O)R ^d are optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, methoxy or oxo; X is N or CR ⁴ ; ^R4 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; 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, 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, 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 is a chemical bond, 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 are each independently 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 they are attached form 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 , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group; R ⁷ is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Z is C(═O) or S(O) ₂ ; L ₁ 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 with one or more ^Re ; 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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, 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; ^R1 is selected from the following groups:

^R2 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 ; ^R3 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 ; ^R4 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; 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 is a chemical bond, CR ⁵ R ⁶ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl is 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 are each independently 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 they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl, oxolanyl or oxhexyl, 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; Y ² is a chemical bond, an acridinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group or a NR ⁷ , wherein the acridinyl group, the tetrahydropyrrolyl group, the piperidinyl group and the morpholinyl group are optionally substituted with one or more deuterium atoms, F, Cl, a cyano group, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a methoxy group, a methylamino group or a dimethylamino group; R ⁷ is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl; Z is C(＝O); L ₁ 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 with one or more ^Re ; 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, SOCH ₃ , SO ₂ CH _{3 , C(═O)CH 3 ,} C(═O)NCH ₃ , NHC(═O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ or P(O)(CH ₂ CH ₃ ) ₂ , wherein the methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, methylamino, ethylamino, SOCH ₃ , SO ₂ CH ₃ , C(═O)CH ₃ , C(═O)NCH ₃ , NHC(=O)CH ₃ , SO ₂ NCH ₃ , P(O)(CH ₃ ) ₂ and P(O)(CH ₂ CH ₃ ) ₂ are optionally substituted with one or more F, Cl, hydroxy, methyl, ethyl, isopropyl or cyclopropyl; G is selected from the following groups:
^R1 is selected from the following groups:

^R2 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:








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. 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 diseases include: 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. 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 the pharmaceutical composition according to claim 9; Preferably, the disease is a tumor disease; More preferably, the tumor diseases include: 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.