CN119320383A

CN119320383A - Nitrogen-containing heteroaryl compound, and preparation method and application thereof

Info

Publication number: CN119320383A
Application number: CN202411234271.3A
Authority: CN
Inventors: 薛海; 石和鹏; 张培龙; 李祥秋; 兰文丽
Original assignee: Beijing Anshi Biotechnology Co ltd
Current assignee: Beijing Anshi Biotechnology Co ltd
Priority date: 2023-09-05
Filing date: 2024-09-04
Publication date: 2025-01-17
Also published as: WO2025051148A1

Abstract

The invention relates to a nitrogen-containing heteroaromatic compound, a preparation method and application thereof, wherein the structure of the nitrogen-containing heteroaromatic compound is shown as a formula I: Wherein M, X, A, E, G, Z, L ₁、L₂、Y¹、Y²、R¹ and R ² are defined as the specification. The nitrogen-containing heteroaromatic compound has high-efficiency and high-selectivity inhibition effect on epidermal growth factor receptor 2 (HER 2), and can be used for treating related diseases induced by HER2 abnormality, in particular to the treatment of cancer diseases.

Description

Nitrogen-containing heteroaryl compound, and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a nitrogen-containing heteroaryl compound, and a preparation method and application thereof.

Background

The epidermal growth factor receptor 2 (HER 2, erbB 2) gene is located on chromosome 17 long arm (17 q 21), is one of four members of the ErbB family (EGFR/HER 1/ErbB1, HER2/ErbB2, HER3/ErbB31 and HER4/ErbB 4), and has tyrosine kinase activity. No ligand has been found that can directly interact with HER2, HER2 can signal downstream MEK/ERK/MAPK pathways and PI3K/AKT bypasses by forming heterodimers with other members of the ErbB family, ultimately promoting cell growth, proliferation, division, etc.

Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been shown to be associated with a number of 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 rate of HER2 overexpression in lung cancer, breast cancer, gastric cancer, bile duct cancer, ovarian cancer and endometrial cancer is about 2.5%,15% -25%, 20%,20%,27% and 18% -80% respectively.

HER2 mutations were detected at approximately 2% -4% in non-small cell lung cancer, with exon 20 insertion mutations accounting for 71% of HER2 mutations, including common subtypes of a772—g775dup (55.0%), G776delinsVC (8.3%), g778_p780dup (5.6%), and G776delinsLC (2.1%). Other HER2 mutations included the 19 th exon mutation L755P (1.9%), the 21 st exon mutation V842I (0.7%), the transmembrane domain mutations V659E (4.1%) and G660D (0.9%), the extracellular domain mutations D277Y (1.9%), S310F (7.7%), S310Y (1.9%) and a466V (1.4%). In addition, studies have shown that patients with aberrant HER2 cancers are more prone to central nervous system metastasis during the course of the disease, and that approximately 47% of non-small cell lung cancer patients with HER2 mutations develop brain metastasis and are associated with poor prognosis.

Drugs currently approved clinically for the treatment of HER2 abnormalities include monoclonal antibodies (mAbs) (trastuzumab, pertuzumab, etc.), small molecule Tyrosine Kinase Inhibitors (TKIs) (lapatinib, fig. calitinib, nadenib, pyrroltinib, etc.), and antibody-coupled drugs (ADCs) (enmetrastuzumab, detrastuzumab).

Monoclonal antibodies and antibody-conjugated drugs have poor selectivity for wild-type EGFR, and are macromolecular drugs that do not readily cross the blood brain barrier, and some patients develop drug resistance or relapse after using monoclonal antibodies (mAbs) for a period of time. Currently approved TKIs have selective TKIs (fig. cartinib) and non-selective TKIs (lapatinib, natatinib, and pyrroltinib) that exhibit moderate antitumor activity against wild-type HER2, but are less effective against the most common HER2 exon 20 insertion mutations. In addition, non-selective TKIs have poor selectivity to wild-type EGFR and are prone to adverse reactions such as rash, diarrhea, etc. Therefore, it is of great importance to develop HER2 inhibitors that are selective, penetrate the blood brain barrier and have a potential inhibitory effect on HER2 exon 20 insertion mutation.

Disclosure of Invention

In order to solve the defects in the prior art, the invention aims to provide a nitrogen-containing heteroaryl compound, a preparation method and application thereof, wherein the nitrogen-containing heteroaryl compound has good activity of inhibiting HER2 No. 20 exon insertion mutation and has higher selectivity to wild EGFR.

The invention is realized by the following technical scheme.

In a first aspect, the present invention provides a compound having the structure shown in formula I below, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, deuterate, N-oxide, prodrug molecule, hydrate, or solvate thereof:

Wherein, in the 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 alkylmercapto, 3-12 membered cycloalkylmercapto, 3-12 membered heterocyclylmercapto, 3-12 membered cycloalkyl-C _1-6 alkylene-mercapto or 3-12 membered heterocyclyl-C _1-6 alkylene-mercapto, said 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 alkyl-mercapto, 3-12 membered cycloalkyl-mercapto, 3-12 membered heterocyclyl-mercapto, 3-12 membered cycloalkyl-C _1-6 alkylene-mercapto and 3-12 membered heterocyclyl-C _1-6 alkylene-mercapto optionally substituted with one or more R';

Y ¹ is a bond, CR ⁵R⁶, a 3-12 membered cycloalkyl or a 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl and 3-12 membered heterocyclyl being optionally substituted with one or more R';

Y ² is a bond, a 3-12 membered heterocyclyl or NR ⁷, said 3-12 membered heterocyclyl optionally substituted with one or more R';

Z is C (=O) or S (O) ₂;

L ₁ is NR ⁸、O、CR⁵R⁶, S, S (O) or S (O) ₂;

L ₂ is a bond, O, NR ⁸、CR⁵R⁶, C (=o), S, S (O), or S (O) ₂;

E is a 6-10 membered aryl or 5-10 membered heteroaryl, said 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted with one or more R ^e;

G is The saidOptionally substituted with one or more R';

- -is no or a single bond;

ring B is 5-6 membered heteroaryl, 5-7 membered heterocyclyl or 5-7 membered cycloalkyl;

X ¹ is a bond, N, CH ₂, O, S, S (O) or S (O) ₂;

X ² is N, CH ₂, O, S, S (O) or S (O) ₂;

X ³ and X ⁴ are each independently N or C, and X ³ and X ⁴ are not both N, and X ¹、X² and X ³ are not both N;

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

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

R ¹ is halomethyl, C _2-4 alkenyl, C _2-4 alkynyl, glycidylyl or C _4-6 cycloalkenyl, said C _2-4 alkenyl, C _2-4 alkynyl, glycidylyl and C _4-6 cycloalkenyl being optionally substituted with one or more halogen, cyano, C _1-4 alkyl, haloC _1-4 alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl, C _1-3 alkoxy-C _1-3 alkyl-or NR ^aR^b, said C _1-4 alkyl, haloC _1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl and C _1-3 alkoxy-C _1-3 alkyl-being optionally substituted with one or more R';

R ² is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C _1-6 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, a 3-12 membered cycloalkyl group or a 3-12 membered heterocyclic group, said hydroxyl group, amino group, C _1-6 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, 3-12 membered cycloalkyl group and 3-12 membered heterocyclic group being optionally substituted with one or more R';

R ³ is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an amino group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _2-4 alkenyl group, c _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, haloC _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^cR^dN-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 alkylmercapto, C _1-6 alkylamino, Di (C _1-6 alkyl) amino, C (=O) NR ^c、NR^cC(＝O)R^d or NR ^cC(＝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 ^cR^dN-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 alkylmercapto, C _1-6 alkylamino and di (C _1-6 alkyl) amino optionally substituted with one or more R';

R ⁴ is a hydrogen atom, halogen, cyano, amino, C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C _1-6 alkylmercapto, C _1-6 alkylamino or di (C _1-6 alkyl) amino, said amino, C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered 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 being optionally substituted by one or more R';

R ⁵ and R ⁶ are each independently a hydrogen atom, halogen, cyano, 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, 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 alkylmercapto, C _1-6 alkylamino, di (C _1-6 alkyl) amino, cyano-C _1-6 alkyl-, C _1-6 alkoxy-C _1-6 alkyl-, 3-12 membered cycloalkyl-C _1-6 alkyl-, or 3-12 membered heterocyclyl-C _1-6 alkyl-, said hydroxy group, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3-to 12-membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, C _1-6 alkylmercapto, C _1-6 alkylamino, Di (C _1-6 alkyl) amino, cyano-C _1-6 alkyl-, C _1-6 alkoxy-C _1-6 alkyl-), 3-12 membered cycloalkyl-C _1-6 alkyl-and 3-12 membered heterocyclyl-C _1-6 alkyl-optionally substituted with one or more R';

Or R ⁵ taken together with R ⁶ and the attached C atom form a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl and 3-12 membered heterocyclyl optionally being substituted with one or more R';

R ⁷ is a hydrogen atom, C _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 haloalkyl, 5-12 membered heteroaryl or 6-12 membered aryl, said C _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 haloalkyl, 5-12 membered heteroaryl and 6-12 membered aryl being optionally substituted by one or more R';

r ⁸ is a hydrogen atom, C _1-6 alkyl, halogenated C _1-6 alkyl, cyano-C _1-6 alkyl-or hydroxyC _1-6 alkyl;

R ^a and R ^b are each independently a hydrogen atom, a C _1-4 alkyl group, a C _1-4 haloalkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group, a 3-12 membered cycloalkyl-C _1-4 alkyl group, a 3-12 membered heterocyclyl-C _1-4 alkyl group, a C _1-4 alkoxy-C _1-4 alkyl group, or a deuterated C _1-4 alkyl group, the C _1-4 alkyl group, the C _1-4 haloalkyl group, the 3-12 membered cycloalkyl group, the 3-12 membered heterocyclyl group, the 3-12 membered cycloalkyl-C _1-4 alkyl group, the 3-12 membered heterocyclyl-C _1-4 alkyl group, the C _1-4 alkoxy-C _1-4 alkyl group, and the deuterated C _1-4 alkyl group being optionally substituted with one or more R';

Or R ^a together with R ^b and the attached N atom form a 3-12 membered heterocyclyl, said 3-12 membered heterocyclyl optionally being substituted with 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-C _1-6 alkyl-or a 3-12 membered heterocyclyl-C _1-6 alkyl-, said C _1-6 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group, a 3-12 membered cycloalkyl-C _1-6 alkyl-and a 3-12 membered heterocyclyl-C _1-6 alkyl-being optionally substituted by one or more R';

R ^e is a deuterium atom, halogen, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy 、OR^e1、SR^e1、SOR^e1、SO₂R^e1、C(＝O)R^e1、C(＝O)NR^e1、C(＝O)OR^e1、NR^e1R^e2、NR^e1C(＝O)R^e2、OC(＝O)R^e1、SONR^e1、SO₂NR^e1、NHS(O)₂R^e1、NHS(O)R^e1、NR^e1C(＝O)OR^e2、NR^e1C(＝O)NR^e2、-(O)(OR^e1)₂ or P (O) (R ^e1)₂, said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 heteroalkenyl, C _2-6 heteroalkynyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, C _1-6 haloalkyl and C _1-6 haloalkoxy optionally substituted with one or more R';

R ^e1 and R ^e2 are each independently a hydrogen atom, a deuterium atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclic group or R ^e1 and R ^e2 together with the attached N atom form a 3-12 membered heterocyclic group;

Each R' is independently a deuterium atom, halogen, cyano, hydroxy, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-4 alkyl, deuterated C _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-4 alkylamino, di (C _1-4 alkyl) amino, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl, halogenated C _1-6 alkoxy or oxo (=o).

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

R ³ is a hydrogen atom, a deuterium atom, F, cl, br, cyano, hydroxy, amino, C _1-6 alkyl, halogenated C _1-4 alkyl, C _2-4 alkenyl, c _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, C _1-6 alkoxy, haloC _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, R ^cR^dN-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 alkylmercapto, C _1-6 alkylamino, Di (C _1-6 alkyl) amino, C (=O) NR ^c、NR^cC(＝O)R^d or NR ^cC(＝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 ^cR^dN-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 alkylmercapto, C _1-6 alkylamino and di (C _1-6 alkyl) amino optionally substituted with one or more R';

R ^c and R ^d are each independently a hydrogen atom, methyl, ethyl, isopropyl or cyclopropyl optionally substituted with one or more R';

r' is a deuterium atom, F, cl, cyano, hydroxy, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or oxo (=o);

preferably, in formula I, M is N or CR ³;

R ³ is a hydrogen atom, a deuterium atom, F, cl, br, cyano group, hydroxy group, amino group, C _1-6 alkyl group, halogenated C _1-4 alkyl group, C _1-6 alkoxy group, cyano group, amino group, C _1-6 alkyl group, halogen-substituted C _1-4 alkyl group, C _1-6 alkoxy group, Halogenated C _1-6 alkoxy, 3-12 membered heterocyclyloxy, R ^cR^dN-C_1-6 alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, C _1-6 alkylmercapto, C _1-6 alkylamino or NR ^cC(＝O)R^d, said hydroxy, amino, C _1-6 alkyl, halogenated C _1-4 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, 3-12 membered heterocyclyloxy, R ^cR^dN-C_1-6 alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, c _1-6 Alkylmercapto, C _1-6 alkylamino and NR ^cC(＝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;

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

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

R ⁴ is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, isopropyl, cyclopropyl, methoxy or cyclopropoxy, said amino, methyl, isopropyl, ethyl, cyclopropyl, methoxy and cyclopropoxy being optionally substituted by one or more R';

R' is deuterium atom, F, cl, cyano, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

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

R ⁴ is a hydrogen atom, halogen, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or cyclopropoxy, said amino, methyl, ethyl, cyclopropyl, methoxy and cyclopropoxy being optionally substituted by one or more R';

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

In certain embodiments, in formula I, a is C _2-4 alkenyl, C _2-4 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C _1-6 alkoxy, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyloxy, 3-12 membered cycloalkyl-C _1-6 alkylene-oxy, or 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, said 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 being 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-dihydro-oxazol, ethoxy, propoxy, piperidinyloxy, tetrahydropyrroloxy, acridinyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, piperidinomethyleneoxy or tetrahydropyrrolmethyleneoxy, 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-dihydro-oxazol, ethoxy, propoxy, piperidinyloxy, tetrahydropyrroloxy, acridinoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy and tetrahydropyrrolmethyleneoxy optionally substituted with one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy substitution.

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 groups.

In certain embodiments, in formula I, Y ¹ is a bond, CR ⁵R⁶, 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl and 3-12 membered heterocyclyl optionally being 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, halogen, cyano, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-10 membered aryl, cyano-C _1-6 alkyl-, C _1-6 alkoxy-C _1-6 alkyl-, C _1-6 alkylamino or 3-12 membered cycloalkyl-C _1-6 alkyl-, said hydroxy, amino, C _1-6 alkyl, halo 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-being optionally substituted by one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

Or R ⁵ and R ⁶ together with the attached C atom form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, said 3-12 membered cycloalkyl and 3-12 membered heterocyclyl optionally being substituted by one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups;

Preferably, in formula I, Y ¹ is a bond, CR ⁵R⁶, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl and morpholinyl being optionally substituted by 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, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl or pyrazolyl, said hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxymethyl, methoxyethyl, acetonitrile, methylamino, cyclopropylmethyl, phenyl and pyrazolyl optionally being 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 or oxyhexyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, oxetanyl and oxetanyl groups are optionally substituted by one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy groups.

In certain embodiments, in formula I, Y ² is a bond, a 3-12 membered heterocyclyl or NR ⁷, said 3-12 membered heterocyclyl optionally being substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, 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 bond, acridinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, or NR ⁷, the acridinyl, tetrahydropyrrolyl, piperidinyl, and morpholinyl groups are optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino, or dimethylamino, and R ⁷ is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, or trifluoroethyl.

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, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, acetonitrile or hydroxy C _1-6 ethyl;

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

r ⁸ is a hydrogen atom, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or acetonitrile group.

In certain embodiments, in formula I, L ₂ is a bond, O, CH, or C (=o).

In certain embodiments, in formula I, E is phenyl or 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl optionally substituted with one or more R ^e;

R ^e is a deuterium atom, F, cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino 、SOCH₃、SO₂CH₃、C(＝O)CH₃、C(＝O)NCH₃、NHC(＝O)CH₃、SO₂NCH₃、P(O)(CH₃)₂ or P (O) (CH ₂CH₃)₂, optionally substituted with one or more F, cl, hydroxy, methyl, ethyl, isopropyl or P (O) (CH ₂CH₃)₂), said 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) (CH ₂CH₃)₂;

Preferably, in formula I, E is phenyl, pyridinyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, said phenyl, pyridinyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole optionally being substituted with one or more R ^e;

R ^e is a deuterium atom, F, cl, cyano, nitro, methyl, ethyl, isopropyl, ethylene, acetylene, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino 、SOCH₃、SO₂CH₃、C(＝O)CH₃、C(＝O)NCH₃、NHC(＝O)CH₃、SO₂NCH₃、P(O)(CH₃)₂ or P (O) (CH ₂CH₃)₂) optionally substituted with one or more F, cl, hydroxy, methyl, ethyl, isopropyl or P (O) (CH ₂CH₃)₂) said 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) (CH ₂CH₃)₂).

In certain embodiments, in formula I, G isOptionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

- -is no or a single bond;

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

X ¹ is a bond, N, CH ₂, S, O, S (O) or S (O) ₂;

X ² is N, CH ₂, O, S, S (O) or S (O) ₂;

x ⁵ is a bond, N, CH ₂, O, or S;

X ⁶ is N, O, S or CH;

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

Optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, deuteromethyl, ethyl, deuteromethyl, 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, glycidyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, said halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, glycidylyl, cyclobutenyl, cyclopentenyl and cyclohexenyl optionally being substituted with one or more F, cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, glycidyl, epoxybutanoyl, deuterium atom, phenyl, pyridinyl or NR ^aR^b, said methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, glycidyl, epoxybutanoyl, phenyl and pyridinyl optionally being 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, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinylmethyl and acridinylethyl being optionally substituted by one or more R';

Or R ^a together with R ^b and the attached N atom forms an acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 7-azabicyclo [2.2.1] heptanyl, 9-azabicyclo [3.3.1] nonanyl, 2-azabicyclo [4.1.0] heptanyl or 2-azabicyclo [3.1.0] hexanyl group, said acridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 7-azabicyclo [2.2.1] heptanyl, 9-azabicyclo [3.3.1] nonanyl, 2-azabicyclo [4.1.0] heptanyl and 2-azabicyclo [3.1.0] hexanyl group optionally substituted with one or more R';

R' is a deuterium atom, F, cl, cyano, hydroxy, amino, methyl, ethyl, vinyl, ethynyl, deuteromethyl, 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, cyano, amino, C _1-4 alkyl, or 3-6 membered cycloalkyl;

Preferably, in formula I, R ² is a hydrogen atom, a deuterium atom, F, cl, cyano, amino, methyl, ethyl, isopropyl or cyclopropyl.

In certain embodiments, in formula I:

M is N or CR ³;

x is N or CR ⁴;

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, said 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 being optionally substituted by one or more R';

Y ¹ is a bond, CR ⁵R⁶, 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl and 3-12 membered heterocyclyl being optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

y ² is a bond, a 3-12 membered heterocyclyl or NR ⁷, said 3-12 membered heterocyclyl optionally being substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

Z is C (=O) or S (O) ₂;

l ₁ is NR ⁸ or O;

L ₂ is a bond, O, CH or C (=o);

E is phenyl or 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl optionally substituted with one or more R ^e;

G is Optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

- -is no or a single bond;

X ¹ is a bond, N, CH ₂, S, O, S (O) or S (O) ₂;

X ² is N, CH ₂, O, S, S (O) or S (O) ₂;

x ⁵ is a bond, N, CH ₂, O, or S;

X ⁶ is N, O, S or CH, or

R ¹ is halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, glycidyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, said halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, glycidyl, cyclobutenyl, cyclopentenyl and cyclohexenyl optionally being substituted with one or more F, cl, methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, glycidyl, epoxybutanyl, deuterium atoms, phenyl, pyridinyl or NR ^aR^b, said methyl, ethyl, cyclopropyl, acridinyl, pyrrolidinyl, piperidinyl, epoxypropynyl, epoxybutanyl, phenyl and pyridinyl optionally being substituted with one or more R';

R' is a deuterium atom, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, vinyl, ethynyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy or oxo (=o);

R ² is a hydrogen atom, a deuterium atom, F, cl, cyano, amino, C _1-4 alkyl or 3-6 membered cycloalkyl.

In other embodiments, in formula I:

M is N or CR ³;

R ³ is a hydrogen atom, a deuterium atom, F, cl, br, cyano group, hydroxy group, amino group, C _1-6 alkyl group, halogenated C _1-4 alkyl group, C _1-6 alkoxy group, cyano group, amino group, C _1-6 alkyl group, halogen-substituted C _1-4 alkyl group, C _1-6 alkoxy group, Halogenated C _1-6 alkoxy, 3-12 membered heterocyclyloxy, R ^cR^dN-C_1-6 alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, C _1-6 alkylmercapto, C _1-6 alkylamino or NR ^cC(＝O)R^d, said hydroxy, amino, C _1-6 alkyl, halogenated C _1-4 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, 3-12 membered heterocyclyloxy, R ^cR^dN-C_1-6 alkylene-oxy, 3-12 membered heterocyclyl-C _1-6 alkylene-oxy, C _1-6 alkylmercapto, C _1-6 alkylamino and NR ^cC(＝O)R^d optionally substituted with one or more deuterium atoms, F, cl, hydroxy, methyl, methoxy or oxo;

x is N or CR ⁴;

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-dihydro-oxazole, ethoxy, propoxy, piperidinyloxy, tetrahydropyrroloxy, acridinoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy or tetrahydropyrrolmethyleneoxy, 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-dihydro-oxazol, ethoxy, propoxy, piperidinyloxy, tetrahydropyrroloxy, acridinoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, piperidinylmethyleneoxy and tetrahydropyrrolmethyleneoxy optionally substituted with one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl, acridinyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy or methoxy substitution;

Y ¹ is a bond, CR ⁵R⁶, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrolyl, piperidinyl or morpholinyl optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxy, methylamino or dimethylamino;

or R ⁵ and R ⁶ together with the attached C atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrole, oxetanyl or oxycyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acridinyl, tetrahydropyrrole, oxetanyl and oxycyclohexyl being optionally substituted by one or more F, cl, methyl, ethyl, isopropyl, cyclopropyl or methoxy;

Y ² is a bond, acridinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, or NR ⁷, the acridinyl, tetrahydropyrrolyl, piperidinyl, and morpholinyl being optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, methylamino, or dimethylamino;

Z is C (=O) or S (O) ₂;

l ₁ is NR ⁸;

R ⁸ is hydrogen atom, methyl, ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or acetonitrile group;

L ₂ is a bond, O, CH or C (=o);

E is phenyl, pyridinyl, pyrimidine, pyridazine, pyrazine, thiophene, or pyrazole, said phenyl, pyridinyl, pyrimidine, pyridazine, pyrazine, thiophene, and pyrazole optionally substituted with one or more R ^e;

G is selected from the following groups:

Optionally substituted with one or more deuterium atoms, F, cl, cyano, hydroxy, amino, methyl, deuteromethyl, ethyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

r ¹ is selected from the following groups:

R ² is a hydrogen atom, a deuterium atom, F, cl, cyano, amino, methyl, ethyl, isopropyl or cyclopropyl.

In still other embodiments, in formula I:

M is N or CR ³;

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

x is N or CR ⁴;

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;

z is C (=o);

l ₁ is NR ⁸;

L ₂ is a bond, O, CH or C (=o);

G is selected from the following groups:

r ¹ is selected from the following groups:

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

In a second aspect, in certain embodiments, the present invention provides a process for preparing a compound of formula I, comprising the reaction steps of (1) coupling or substitution reaction of compound I-1 with compound I-2 to form compound I-3;

(2) The compound I-3 and the compound I-4 undergo coupling or substitution reaction to form a compound I-5;

(3) Deprotection of compound I-5 to form compound I-6;

(4) The compound I-6 and the compound I-7 undergo condensation reaction to form a compound shown in a formula I;

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

the compound I-3 and the compound I-8 undergo coupling or substitution reaction to form a compound shown in a formula I;

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

The compound I-9 and the compound I-10 undergo coupling or substitution reaction to form a compound I-3;

Wherein M, X, A, E, G, Z, L ₁、L₂、Y¹、Y²、R¹ and R ² are as defined above, H is a hydrogen atom, X ^a is a chlorine atom, X ^b is a bromine atom, an iodine atom or a hydroxyl group, X ^c is hydrogen, halogen, OMs, -B (OH) ₂ or X ^d is a bromine atom or an iodine atom, G ^a is Boc, and G ^b is Cl, OH or-O-Z-R ¹.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, deuterate, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient;

Preferably, the pharmaceutical composition is in the form of a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, or spray.

In a fourth aspect, the invention provides the use of a compound as described above or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, deuteride, N-oxide, prodrug molecule, hydrate or solvate thereof or a pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, deuteride, N-oxide, prodrug molecule, hydrate or solvate thereof, or a pharmaceutically acceptable carrier or excipient, for the treatment of a HER2 disorder-mediated disease;

preferably, the disease is a neoplastic disease;

More preferably, the neoplastic disease comprises 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 tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis, or pulmonary fibrosis.

In a fifth aspect, the present invention provides a method of treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, deuterate, N-oxide, prodrug molecule, hydrate, or solvate thereof, or a pharmaceutical composition.

The patient is preferably a mammal, preferably a human.

In certain embodiments, the mode of administration includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral, vaginal, peritoneal, bladder, nasal administration.

In certain embodiments, the tumor comprises a head-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's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

The compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopic labels, deuterated, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof, may be administered into the organism by any suitable route, such as by oral, intravenous, intranasal, topical, intramuscular, intradermal injection, transdermal administration or subcutaneous route.

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

Suitable dosage forms include, but are not limited to, dosage forms for injectable use 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 administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, pharmaceutical patches and inhalants, dosage forms for vaginal or rectal administration such as suppositories. These dosage forms may be prepared under appropriate conditions and with suitable excipients, and methods and processes are well known, such as provided by Remington, at 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 comprises an 18-21 exon mutation, a transmembrane domain mutation and an extracellular domain mutation, wherein the mutation comprises a point mutation, a deletion mutation and an insertion mutation;

More preferably, the exon 20 insertion mutation comprises a 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 mutation comprising G776C, G776D, G776S, G776V, V777L, D778H, V782I, T791A, L806P, R811L, N813T, R816C, Q820K, Q828H.

In certain embodiments, the compounds or pharmaceutical compositions of the present invention may be administered simultaneously with one or more additional pharmacologically active agents, which may provide a additive or even synergistic effect in vivo. For example, the compounds of the present invention may be combined with additional pharmacologically active agents into one pharmaceutical composition, or administered simultaneously as separate compositions, or sequentially as separate compositions. additional pharmacologically active agents that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to, 1) EGFR family inhibitors, mono/diabodies or ADCs, and the like, such as octenib, almitinib, vomittinib, bei Futi b, olmutinib, lazertinib, PLB b, afatinib, dacatinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, lenatinib, icotinib, trastuzumab, pertuzumab, margetuximab, enmelittuzumab, Trastuzumab, etc., 2) downstream pathway or other pathway target inhibitors mono/diabodies or ADCs, etc., including but not limited to MEK, RET, PI K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (e.g., CDK 4/6), etc. Such as trametinib, bimatinib, semitinib, lapatinib, ideranib, copanlisib, duvelisib, alpelisib, umbralisib, parsaclisib, rapamycin, temsirolimus, everolimus, carbamatinib, terbutanib, sivanitinib, gu Meiti, beritinib, cabatinib, emibetuzumab, telisotuzumab, nilapatinib, pamatinib, rebamipinib, abemaciclib, etc., 3) an anti-angiogenic agent such as bevacizumab, afliberpupi, tizotinib, etc, Ramopirudin, nidamib, etc., 4) apoptosis inducing agents (e.g., bcl-2), such as obatoclax, venezuril, etc., 5) chemotherapeutic agents, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecine, capecitabine, carboplatin, cisplatin, carmustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, positive-going clindamycin, feigiostin, fludarabine, fludrocortisone fluoxymesterone, flutamide, fluoxymesterone, fluo febuxostat, fludarabine, fludrocortisone, fluoxymesterone, flutamide, fludarabine, flu gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride Tuopregine, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole, leucovorin, prastatin, mithramycin, procarbazine, raltitrexed, porphin sodium, rituximab, streptozocin, suramin, leuprorelin, levamisole, cyclohexa-nitrourea, nitrogen mustard, Medroxyprogesterone, megestrol, melphalan, mercaptopurine, sodium thioethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triaminophos, methyl chloride, topotecan Kang Ermao titanium, retinoic acid, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

In certain embodiments, the compounds provided herein may be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors such as Du Walu mAbs, tumor cell multidrug resistance reversal agents (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine and monoclonal antibodies.

In certain embodiments, the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein may be administered concurrently with radiation therapy. In certain embodiments, the compounds provided herein may be used in conjunction with surgery, tumor thermal therapy, ultrasound focus therapy, cryotherapy, or several of the above.

The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

It is particularly pointed out that similar substitutions and modifications to the invention will be apparent to those skilled in the art, which are all deemed to be included in the invention. It will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, or in the appropriate variations and combinations, without departing from the spirit and scope of the invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention.

The invention is carried out according to the conventional conditions or the conditions suggested by manufacturers if the specific conditions are not noted, and the raw materials or auxiliary materials and the reagents or instruments are conventional products which can be obtained commercially if the manufacturers are not noted.

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 invention.

Representing the ligation site.

The minimum and maximum values of carbon atom content in the hydrocarbon groups are indicated by a prefix, e.g., the prefix (C _a-b) alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C _1-6) alkyl refers to alkyl groups containing from 1 to 6 carbon atoms. The alkyl group is branched or straight chain.

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

"Alkyl" refers to a straight 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 the like. C _1-8 alkyl is preferred. More preferably a C _1-6 alkyl group. More preferably a C _1-4 alkyl group.

The alkyl groups being optionally substituted or unsubstituted, the substituted substituents preferably being one or more of deuterium atoms, halogens, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, deuterated C _1-10 alkyl, deuterated C _1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=o), -C _0-6 alkyl-OR ^e1、-C_0-6 alkyl-SR ^e1、-C_0-6 alkyl-SOR ^e1、-C_0-6 alkyl-SO ₂R^e1、-C_0-6 alkyl-C (=o) R ^e1、-C_0-6 alkyl-C (=o) NR ^e1、-C_0-6 alkyl-C (=o) OR ^e1、-C_0-6 alkyl-NR ^e1R^e2、-C_0-6 alkyl-NR ^e1C(＝O)R^e2、-C_0-6 alkyl-OC (=o) R ^e1、-C_0-6 alkyl-sonor ^e1、-C_0-6 alkyl-SO ₂NR^e1、-C_0-6 alkyl-NHS (O) ₂R^e1、-C_0-6 alkyl-NHS (O) R ^e1、-C_0-6 alkyl-NR ^e1C(＝O)OR^e2、-C_0-6 alkyl-NR ^e1C(＝O)NR^e2、-C_0-6 alkyl- (O) (OR ^e1)₂ and-C _0-6 alkyl-P (O) (R ^e1)₂.

"Cycloalkyl" refers to a saturated, monocyclic or polycyclic, cyclic hydrocarbon group, which can be combined with other groups. Monocyclic cyclic hydrocarbon groups include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 3-8 membered cycloalkyl is preferred. More preferably 3-6 membered cycloalkyl. More preferably 3-4 membered cycloalkyl. Polycyclic cyclic hydrocarbyl includes bicyclic, spiro, fused or bridged cyclic aliphatic hydrocarbyl groups including, but not limited to, the following groups:

"cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon group having at least one carbon-carbon double bond, but which does not form a fully conjugated pi-electron system, and can be combined with other groups. Monocyclic cycloalkenyl includes, but is not limited to, as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, and the like. Preferably 3-8 membered cycloalkenyl. More preferably 3-6 membered cycloalkenyl. More preferably a 5-6 membered cycloalkenyl group. Polycyclic cycloalkenyl includes bicyclic, spiro, fused, or bridged cycloalkenyl groups. Including but not limited to the following groups:

The cycloalkyl or cycloalkenyl groups may be fused aryl, heteroaryl, or heterocyclyl groups including, but not limited to, tetrahydronaphthyl, 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 ethenyl, propenyl, (E) -2-methyl vinyl, (Z) -2-methyl vinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, and (Z) -but-1-enyl. C _2-6 alkenyl is preferred. More preferably a C _2-4 alkenyl group.

"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. C _2-6 alkynyl is preferred. More preferably a C _2-4 alkynyl group.

"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 with the same or different halogens. Including, but not limited to, e.g., -CH ₂Cl,-CHF₂,-CH₂CF₃,-CH₂CCl₃, perfluoroalkyl (e.g., -CF ₃), and the like.

"Alkylamino" refers to an alkyl-substituted NH ₃. 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 carbocyclic ring system having one or more fused or unfused aromatic rings, including, but not limited to, e.g., phenyl, naphthyl, indenyl. Preferably 6-10 membered monocyclic or bicyclic aromatic groups. More preferably phenyl or naphthyl. Most preferred is phenyl.

"Heterocyclyl" refers to a group of a 4-12 membered non-aromatic mono-or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings having only a single bond and unsaturated rings having at least one double bond (c= C, C =n or n=n), but not forming a fully conjugated pi-electron system. Wherein the heteroatoms are independently selected from N, O, S, nitric Oxide (NO), sulfoxide, S (O) (=nh), and sulfone groups. Polycyclic ring systems include fused, bridged or spiro ring systems. Examples of monocyclic heterocyclyl moieties include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and the like. Preferably a 4-7 membered heterocyclyl. More preferably a 4-6 membered heterocyclic group. 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 [5.1.0] octyl, hexahydro-1H-pyrrolo [3,4-b ] pyrrolyl, hexahydro-1, 4-aza-pyrrolo [3.2.1] octyl, 8-oxa-3-aza-spiro [3.2.1] octyl, 8-diaza-3-azabicyclo [3.2.1] spiro [ 3.1 ] octyl, 8-azabicyclo [3.2.1] hexahydro-oxa-3-oxa-5-oxa-1 ] spiro [3.2.1] octyl, 8-azabicyclo [3.2.1] spiro [ 3.1 ] carbonyl, 3-azabicyclo [3.2.1] octyl, 3-azabicyclo [3.2.1] carbonyl, 3-azabicyclo [ 3.1 ] carbonyl, 3-azabicyclo [ 3] carbonyl, 3-azabicyclo [ 3.3.3 ] carbonyl, 3-azabicyclo [3 carbonyl ] carbonyl. Examples of unsaturated heterocyclyl moieties include, but are not limited to:

The heterocyclic group being optionally substituted or unsubstituted, the substituted substituents preferably being one or more of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, deuterated C _1-10 alkyl, deuterated C _1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=o), -C _0-6 alkyl-OR ^e1、-C_0-6 alkyl-SR ^e1、-C_0-6 alkyl-SOR ^e1、-C_0-6 alkyl-SO ₂R^e1、-C_0-6 alkyl-C (=o) R ^e1、-C_0-6 alkyl-C (=o) NR ^e1、-C_0-6 alkyl-C (=o) OR ^e1、-C_0-6 alkyl-NR ^e1R^e2、-C_0-6 alkyl-NR ^e1C(＝O)R^e2、-C_0-6 alkyl-OC (=o) R ^e1、-C_0-6 alkyl-sonor ^e1、-C_0-6 alkyl-SO ₂NR^e1、-C_0-6 alkyl-NHS (O) ₂R^e1、-C_0-6 alkyl-NHS (O) R ^e1、-C_0-6 alkyl-NR ^e1C(＝O)OR^e2、-C_0-6 alkyl-NR ^e1C(＝O)NR^e2、-C_0-6 alkyl- (O) (OR ^e1)₂ and-C _0-6 alkyl-P (O) (R ^e1)₂.

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

Heteroaryl is optionally substituted or unsubstituted, the substituted substituents preferably being one or more of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, deuterated C _1-10 alkyl, deuterated C _1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=o), -C _0-6 alkyl-OR ^e1、-C_0-6 alkyl-SR ^e1、-C_0-6 alkyl-SOR ^e1、-C_0-6 alkyl-SO ₂R^e1、-C_0-6 alkyl-C (=o) R ^e1、-C_0-6 alkyl-C (=o) NR ^e1、-C_0-6 alkyl-C (=o) OR ^e1、-C_0-6 alkyl-NR ^e1R^e2、-C_0-6 alkyl-NR ^e1C(＝O)R^e2、-C_0-6 alkyl-OC (=o) R ^e1、-C_0-6 alkyl-sonor ^e1、-C_0-6 alkyl-SO ₂NR^e1、-C_0-6 alkyl-NHS (O) ₂R^e1、-C_0-6 alkyl-NHS (O) R ^e1、-C_0-6 alkyl-NR ^e1C(＝O)OR^e2、-C_0-6 alkyl-NR ^e1C(＝O)NR^e2、-C_0-6 alkyl- (O) (OR ^e1)₂ and-C _0-6 alkyl-P (O) (R ^e1)₂.

"Bridged ring" means a polycyclic group wherein any two rings share two atoms not directly attached, may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, and the ring atoms may be all carbon atoms or wherein one or more of the ring atoms are selected from the group consisting of N, O, S, SO, or SO ₂. Preferably 7-10 rings.

"Spiro" refers to a polycyclic group wherein any two rings share a carbon atom, may contain one or more double bonds, but none of the rings has a fully conjugated pi-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 5-10 rings.

Condensed ring means a polycyclic group in which each ring shares two adjacent atoms with the other rings in the system.

The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

One cyclic group may be bonded to another group in a variety of ways. If the bonding means is not explicitly defined, the representation includes all possible means. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, while "thienyl" includes 2-or 3-thienyl.

"Alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. C _1-8 alkoxy is preferred. More preferably a C _1-6 alkoxy group. More preferably a C _1-4 alkoxy group.

"Cycloalkoxy" refers to-O-cycloalkyl, wherein cycloalkyl is as described above. C _3-8 cycloalkoxy is preferred. Including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

"Heterocyclyloxy" means an-O-heterocyclyl group, wherein the heterocyclyl group is as described above. Including but not limited to azetidinyloxy, oxetyloxy, pyrrolidinyloxy, cyclohexyloxy, piperidinyloxy, and the like.

"Pharmaceutically acceptable salts" refers to conventional acid or base addition salts which retain the biological effectiveness and properties of the compounds of formula I, formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids. 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, hydroxyethanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid and the like. Examples of base addition salts include those derived from inorganic acids and from organic acids, such as ammonium, calcium, ferric, aluminum, sodium, potassium, zinc, magnesium salts. The organic base includes salts of primary, secondary and tertiary amines such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, and the like. Chemical modification of pharmaceutical compounds (i.e., drugs) to salts is a technique well known to the pharmaceutical chemist to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds.

"Prodrug molecule" refers to a prodrug that can be converted in vivo to the structure of a compound of the invention and pharmaceutically acceptable salts thereof.

"N-oxide" means that when an amine functional group or an N-containing heteroaryl compound is contained in the compound, 1 or more than 1N atoms can be oxidized to form an N-oxide containing N ⁺ compound, preferably an N-oxide of a tertiary amine or an N-oxide of an N-containing heteroaryl.

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

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

"Pharmaceutical composition" means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is admixed with other chemical ingredients, such as a pharmaceutically acceptable carrier, excipient or diluent. The purpose of the pharmaceutical composition is to facilitate the process of administration to animals. The pharmaceutical composition may include pharmaceutically acceptable excipients to mimic physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

By "pharmaceutically acceptable carrier" is meant a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or potting material, which participates in the loading or transfer of 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. The pharmaceutically acceptable carrier may be a medium, diluent, excipient or other material that is not overly toxic or otherwise adverse to the animal tissue and that can be used to contact the animal tissue.

Some pharmaceutically acceptable carriers include (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, (3) celluloses and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, (4) tragacanth powder, (5) maltose, (6) gelatin, (7) talc, (8) excipients such as cocoa butter and suppository waxes, (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols such as propylene glycol, (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol, (12) lipids such as ethyl oleate, ethyl laurate, (13) agarose, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) sterile pyrogen water, (17) physiological saline, (18) ringer's solution, (19) alcohols such as ethanol and propanol, (20) phosphate buffer, (21) other substances which are non-toxic and compatible in pharmaceutical dosage forms such as acetone.

Each pharmaceutically acceptable carrier should be compatible with the other ingredients, e.g., formulation with the compounds provided herein, without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio, for a living organism tissue or organ.

The pharmaceutical ingredients may be formulated into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). Methods and processes for preparing pharmaceutical compositions are well known and may be prepared according to conventional techniques, such as provided in Remington,The Science and Practice of Pharmacy(Gennaro ed.20th edition,Williams&Wilkins PA,USA)(2000).

Detailed Description

First set of preparation examples preparation of intermediates A1-A28

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

First step 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), followed by addition of potassium carbonate (1.9 g,13.4 mmol) and 2-chloro-1-fluoro-4-nitrobenzene (1.18 g,6.75 mmol) and stirring at room temperature for 1H. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-76% as eluent to give 5- (2-chloro-4-nitrophenoxy) -1-methyl-1H-benzimidazole (yellow solid, 1.8g, 87.8%). MS (ESI ⁺)m/z＝304.1[M+H]⁺. This step potassium carbonate may also be replaced with cesium carbonate or sodium carbonate.

Second step 3-chloro-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline

A mixed solution of 5- (2-chloro-4-nitrophenoxy) -1-methyl-1H-benzimidazole (1.8 g,5.9 mmol) in methanol (10 mL) and water (2 mL) was added iron powder (1.6 g,29.5 mmol) and ammonium chloride (3.2 g,59.0 mmol) in this order, nitrogen was replaced, and the temperature was raised to 60℃and stirred for 1H. The reaction solution was cooled to room temperature. The filtrate was filtered, concentrated under reduced pressure, the residue was added with water (20 mL), extracted with dichloromethane (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 3-chloro-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline (yellow solid, 1.5g,92.5%, crude). MS (ESI ⁺)m/z＝274.2[M+H]⁺).

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 temperature was raised to 80℃and stirred for 1H. Cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of methanol/dichloromethane (0-10%) to give 5- ((4- ((5-iodopyrimidin-4-yl) amino) -2-chlorophenyl) oxy) -1-methyl-1H-benzimidazole (yellow solid, 400mg, 45.8%). MS (ESI ⁺)m/z＝478.9[M+H]⁺).

Preparation of intermediates A2-A8, A19-A26

The intermediate A2-A8 and the intermediate A19-A26 are prepared by taking commercial aryl/heteroaryl phenol and halogenated aryl/heteroaryl nitro compounds or halogenated heteroaryl and aryl/heteroaryl nitro phenol compounds as raw materials and adopting an intermediate A1 synthesis method (or taking 1, 4-dioxane as a solvent and N, N-diisopropylethylamine or triethylamine as a catalyst under the reaction condition of 60-90 ℃). As shown in table 1.

TABLE 1 intermediates A2-A8, A19-A26

Preparation of intermediate A9.5-iodo-6-methyl-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-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 absolute ethanol (5 mL), 4-chloro-5-iodo-6-methylpyrimidine (300 mg,1.2 mmol) and methylsulfonic acid (11.3 mg,0.12 mmol) were added, and the mixture was heated to 70℃and stirred for 1H. The reaction mixture was cooled to room temperature, quenched with water (5 mL), made alkaline with sodium bicarbonate, extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography eluting with a gradient of methanol/dichloromethane=0-10% as eluent to give 5-iodo-6-methyl-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (brown oil, 323 mg, 94.1%). MS (ESI ⁺)m/z＝472.1[M+H]⁺).

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

5-Bromo-6-chloropyrimidin-4-amine (500 mg,2.4 mmol) was dissolved in tert-butanol (8 mL) at 0deg.C, 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 100deg.C and stirred for 1H. After the reaction is finished, cooling to room temperature, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by column chromatography eluting with methanol/dichloromethane=0-10% gradient as eluent to give 5-bromo-6- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-4-amine (yellow solid, 950mg, 93.1%). MS (ESI ⁺)m/z＝425.0[M+H]⁺).

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

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

Preparation of intermediate A12.5-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 A5,300mg,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, and the temperature was raised to 100℃and stirred for 1H. Cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (50 ml×3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue purified by separation on a silica gel column with methanol/dichloromethane=0-15% as eluent to give 5-iodo-N ⁴ - (2-methoxyethyl) -N ⁶ - (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidine-4, 6-diamine (tan solid 125mg, 38.6%). MS (ESI ⁺)m/z＝531.1[M+H]⁺).

Preparation of intermediate A13.5-iodo-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) -6-methylsulfanyl pyrimidin-4-amine

6-Chloro-5-iodo-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (intermediate A5,500mg,1.0 mmol) was dissolved in N, N-dimethylformamide (20 mL), sodium methyl mercaptide (213.7 mg,3.0 mmol) was added, and the mixture was warmed to 110℃and stirred for 5H. Cooled to room temperature, distilled under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel chromatography column using methanol/dichloromethane=10% as eluent to give 5-iodo-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) -6-methylsulfanyl pyrimidin-4-amine (light yellow solid, 450mg, 87.9%). MS (ESI ⁺)m/z＝504.0[M+H]⁺).

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

The first step is N, 3-dimethyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline

3-Methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline (2 g,7.9 mmol) was dissolved in toluene (40 mL), paraformaldehyde (0.28 g,9.48 mmol) and palladium on carbon (0.84 g,7.9 mmol) were added, nitrogen was replaced, and the temperature was raised to 60℃and stirred for 2H. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the combined phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol/dichloromethane=0-10% as eluent to give 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]⁺).

Second step 5-iodo-N-methyl-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine

N, 3-dimethyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline is taken as a raw material, and 5-iodo-N-methyl-N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine is prepared according to the method for synthesizing intermediate A9. MS (ESI ⁺)m/z＝472.1[M+H]⁺).

Preparation of intermediate A15.4- ((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 mixture was stirred for 2h at 60 ℃. Cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (methanol/dichloromethane=0-35%) to give 4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-ol (yellow solid, 800mg, 20.0%). MS (ESI ⁺)m/z＝348.2[M+H]⁺).

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

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

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

First step 5-bromo-6- (difluoromethyl) pyrimidin-4-ol

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

Second step 5-bromo-4-chloro-6- (difluoromethyl) pyrimidine

To a 40mL single-necked flask was added 5-bromo-6- (difluoromethyl) pyrimidin-4-ol (1.2 g,5.3 mmol), phosphorus oxychloride (10 mL) was slowly added dropwise under ice-bath, nitrogen was replaced, and the temperature was raised to 90℃and stirred for 1h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 5-bromo-4-chloro-6- (difluoromethyl) pyrimidine (yellow oil, 1.2g,92.42%, crude).

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

Starting from 5-bromo-4-chloro-6- (difluoromethyl) pyrimidine and 3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline, 5-bromo-6- (difluoromethyl) -N- (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidin-4-amine was prepared according to the third step synthesis of intermediate A1 (yellow solid). 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

First step 3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenol

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

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

To a 40mL reaction flask was added 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) in this order, and the mixture was stirred at 90℃for 1H. Quench with water (15 mL), extract with ethyl acetate (40 mL x 3), combine the organic phases and wash with water (40 mL x 3), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and isolate and purify the residue by silica gel column chromatography with methanol/dichloromethane=0-10% as eluent to give 5- (4- ((5-iodopyrimidin-4-yl) oxy) -2-methylphenoxy) -1-methyl-1H-benzo [ d ] imidazole (tan oil, 360mg, 90.8%). MS (ESI ⁺)m/z＝459.2[M+H]⁺).

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

In the first step, 7-bromoimidazo [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), lithium hydroxide monohydrate (899.6 mg,21.4 mmol), N, N' -bis (4-hydroxy-2, 6-dimethylphenyl) oxamide (BHMPO, 66.9mg,0.2 mmol) and copper acetylacetonate (53.2 mg,0.2 mmol) were added in this order under nitrogen atmosphere, and the mixture was stirred at 80℃for 2 hours. After completion of the reaction, the reaction mixture was extracted with methylene chloride/methanol (3/1 v/v,30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using methanol/methylene chloride (15%) as an eluent to give imidazo [1,2-a ] pyridin-7-ol (yellow oil, 1.0g, 73.2%). MS (ESI ⁺)m/z＝157.1[M+Na+H]⁺).

In a second step, imidazo [1,2-a ] pyridin-7-ol (1.0 g,7.45 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (4.9 g,14.91 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.2 g,7.45 mmol) were added sequentially. The temperature is raised to 80 ℃ and stirred for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography eluting with methanol/dichloromethane (15%) as an eluent to give 7- (2-methyl-4-nitrophenoxy) imidazo [1,2-a ] pyridine (pale yellow solid, 1.1g, 55.0%). MS (ESI ⁺)m/z＝270.0[M+H]⁺).

In the third step, 7- (2-methyl-4-nitrophenoxy) imidazo [1,2-a ] pyridine (1.0 g,3.71 mmol) is dissolved in acetonitrile (15 mL) and N-chlorosuccinimide (595.1 mg,4.46 mmol) is added. Stirring for 16h at room temperature. After completion of the reaction, water (30 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography eluting with ethyl acetate/petroleum ether (35%) as an eluent to give 3-chloro-7- (2-methyl-4-nitrophenoxy) imidazo [1,2-a ] pyridine (yellow solid, 360mg, 31.9%). MS (ESI ⁺)m/z＝304.1[M+H]⁺).

The fourth and fifth steps were prepared N- (4- ((3-chloroimidazo [1,2-a ] pyridin-7-yl) oxy) -3-methylphenyl) -5-iodopyrimidin-4-amine (yellow oil, 250mg, 55.2%) according to the methods of the second and third steps of intermediate A1 starting from 3-chloro-7- (2-methyl-4-nitrophenoxy) imidazo [1,2-a ] pyridine. MS (ESI ⁺)m/z＝478.0[M+H]⁺).

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

6-Chloro-5-iodo-N- (3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (intermediate A5,1g,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 to a 100mL reaction flask under nitrogen atmosphere, stirred for 2H at 120℃until the reaction was completed, cooled to room temperature, the reaction mixture was slowly poured into water (50 mL), filtered, the filtrate was extracted with ethyl acetate (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography eluting with a gradient of dichloromethane/methanol (0-10%) to give 5-iodo-N ⁴ -methyl-N ⁶ - (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidine-4, 6-diamine (yellow-like solid, 600mg, 58.8%). MS (ESI ⁺)m/z＝487.0[M+H]⁺).

Second group of preparation examples preparation of intermediates B1-B22

Preparation of intermediate B1, 2-ethynylazetidine-1-carboxylic acid tert-butyl ester

First step, tert-butyl 2- (hydroxymethyl) azetidine-1-carboxylate

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

Second step 2-formyl azetidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2- (hydroxymethyl) azetidine-1-carboxylate (3.0 g,16.0 mmol) was dissolved in dichloromethane (100 mL), and dess-Martin oxidant (13.6 g,32.0 mmol) was added and stirred at room temperature for 1h. The reaction was quenched with aqueous sodium bicarbonate (50 mL), filtered, the filtrate extracted with dichloromethane (200 mL. Times.3), and the combined organic phases were washed with saturated sodium bicarbonate (50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give tert-butyl 2-formylazetidine-1-carboxylate (white solid, 2.4g, 80.9%).

Third step, 2-ethynyl azetidine-1-carboxylic acid tert-butyl ester

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

Preparation of intermediate B2- (1-cyclopropyl-2-yn-1-yl) carbamic acid tert-butyl ester

The intermediate B2 is prepared by adopting the synthesis method of the intermediate B1 by taking commercial 2- ((tert-butoxycarbonyl) amino) -2-cyclopropylacetic acid methyl ester as a raw material.

Preparation of intermediate B3- (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

First step (2S) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

(2S) -2-methyl-1-tert-Butoxycarbonylpyrrolidine-2-carboxylic acid (500 mg,2.2 mmol) was dissolved in dichloromethane (10 mL), 4- (piperidin-1-yl) pyridine (566 mg,3.5 mmol) and 4- (piperidin-1-yl) -1-trifluoromethylsulfonylpyridine-1-ium (1.1 g,3.7 mmol) were added sequentially, 4, 5-tetramethyl-1, 3, 2-dioxaborane (307.0 mg,2.4 mmol) was added rapidly at room temperature, nitrogen displacement was performed, and stirring was continued at room temperature for 10min. After completion of the TLC monitoring the reaction, the reaction was quenched with water (5 mL), the mixture was extracted with dichloromethane (10 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether (0-50%) as eluent to give (2S) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (colorless transparent liquid 312mg, 67.1%). MS (ESI ⁺)m/z＝158.2[M-56]⁺).

Second step (2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

(2S) -2-ethynyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (yellow oil, 140mg, 47.2%) was prepared according to the second step of intermediate B1, starting from (2S) -2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester.

Preparation of intermediate B4-B16

The intermediate B4-B16 is prepared by taking commercial acid or aldehyde compound as a raw material and adopting a synthesis method of the intermediate B3. As shown in table 2.

TABLE 2 intermediates B4-B16

Preparation of intermediate B17.2-ethynyl-5-methylpiperidine-1-carboxylic acid tert-butyl ester

First step 2-formyl-5-methylpiperidine-1-carboxylic acid tert-butyl ester

3-Methylpiperidine-1-carboxylic acid tert-butyl ester (1.0 g,5.0 mmol) was dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, N, N, N ', N' -tetramethylethylenediamine (874.7 mg,7.5 mmol) was added at-78℃and sec-butyllithium (353.6 mg,5.5 mmol) was slowly added dropwise, stirring was maintained at-78℃for 30min, then N, N-dimethylformamide (1.0 g,15.1 mmol) was added dropwise, stirring was continued at-78℃for 1h, quenching with aqueous ammonium chloride (10 mL), the mixture was extracted with ethyl acetate (40 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-50% as eluent to give tert-butyl 2-formyl-5-methylpiperidine-1-carboxylate (colorless transparent liquid, 445mg, 39.0%). MS (ESI ⁺)m/z＝172.2[M-56]⁺).

Second step 2-ethynyl-5-methylpiperidine-1-carboxylic acid tert-butyl ester

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

Preparation of intermediate B18.2-ethynyl-6-methylpiperidine-1-carboxylic acid tert-butyl ester

From tert-butyl 2-methylpiperidine-1-carboxylate, tert-butyl 2-ethynyl-6-methylpiperidine-1-carboxylate (398 mg, 81.0%) was prepared according to the method of synthesis of intermediate B17.

Preparation of intermediate B19, propyl-2-yn-1-yl (2, 2-trifluoroethyl) carbamic acid tert-butyl ester

Tert-butyl (2, 2-trifluoroethyl) carbamate (300 mg,1.5 mmol) was dissolved in tetrahydrofuran (5 mL), nitrogen was replaced, sodium hydride (90.4 mg,3.8 mL) was added at 0℃and stirred at room temperature for 30min, propargyl bromide (215 mg,1.8 mmol) was added dropwise and stirred at room temperature for 3h. After completion of the TLC monitoring, the reaction was quenched by addition of water (5 mL), the mixture was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl propyl-2-yn-1-yl (2, 2-trifluoroethyl) carbamate (colorless oil, 280 mg).

Preparation of intermediate B20 cyclopropyl (propyl-2-alkynyl-1-yl) carbamic acid tert-butyl ester

Tert-butyl cyclopropyl (propyl-2-alkynyl-1-yl) carbamate (colorless oil, 578mg, 93.1%) was prepared according to the synthesis method of intermediate B19, starting from tert-butyl cyclopropyl carbamate. MS (ESI ⁺)m/z＝196.2[M+H]⁺).

Intermediate B21- (1-ethynyl cyclopropyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (1-ethynyl cyclopropyl) (methyl) carbamate (colorless oil) was prepared by the synthesis method of intermediate B19, starting with tert-butyl (1-ethynyl cyclopropyl) carbamate.

Preparation of intermediate B22- (1-phenylpropyl-2-alkynyl-1-yl) carbamic acid tert-butyl ester

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 stirred at room temperature for 1h. The reaction was quenched with water (1 mL), extracted with dichloromethane (6 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-50% as eluent to give tert-butyl (1-phenylpropyl-2-alkynyl-1-yl) carbamate (pale yellow oil, 135.1mg, 73.7%). MS (ESI ⁺)m/z＝331.3[M+H]⁺).

Third group of preparation examples, preparation of intermediates C1-C6

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

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

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

Second step 3- ((2S) -pyrrolidin-2-yl) prop-2-enoic acid ethyl ester

To a 50mL reaction flask was added (2S) -2- (3-ethoxy-3-oxoprop-1-en-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g,9.7 mmol) and a solution of hydrogen chloride in 1, 4-dioxane (20 mL) and stirred at room temperature for 1h. After completion of the TLC monitoring the reaction, concentration under reduced pressure gave ethyl 3- ((2S) -pyrrolidin-2-yl) prop-2-enoate (yellow oil, 2.0g,91.8% crude). MS (ESI ⁺)m/z＝170.1[M+H]⁺).

Third step 3- ((2S) -1-methylpyrrolidin-2-yl) prop-2-enoic acid ethyl ester

Ethyl 3- ((2S) -pyrrolidin-2-yl) prop-2-enoate (1.0 g,5.9 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (70.9 mg,3.0 mmol) was added under ice-bath, stirred for 30min, then methyl iodide (838.8 mg,5.9 mmol) was added, nitrogen was replaced, and stirring was performed at room temperature for 1h. After completion of the TLC monitoring the reaction, the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-50% as eluent to give ethyl 3- ((2S) -1-methylpyrrolidin-2-yl) prop-2-enoate (yellow oil, 279.0mg, 25.0%).

Fourth step 3- ((2S) -1-methylpyrrolidin-2-yl) prop-2-enoic acid

To a 40mL reaction flask was added 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) in this order, nitrogen was replaced, and the mixture was stirred at room temperature for 4 hours. Concentrated under reduced pressure, the residue was added with water (50 mL), ph=2 was adjusted with HCl solution, the mixture was extracted with ethyl acetate (50 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-50% as eluent to give 3- ((2S) -1-methylpyrrolidin-2-yl) prop-2-enoic acid (yellow oil, 170mg, 59.5%). MS (ESI ⁺)m/z＝156.1[M+H]⁺).

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

3- (1-Methylpyrrolidin-2-yl) prop-2-enoic acid (yellow oil) is prepared by taking tert-butyl 2-formylpyrrolidine-1-carboxylate as a raw material according to a method for synthesizing an intermediate C1. MS (ESI ⁺)m/z＝156.1[M+H]⁺).

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

Dimethyl (prop-2-yn-1-yl) amine (400 mg,4.81 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to-40℃and n-butyllithium (770.6 mg,12.0 mmol) was added, stirred for 0.5h, at which point dry ice (2.0 g) was added. Slowly warm to room temperature and stir for 0.5h. Concentrating under reduced pressure at low temperature, and lyophilizing to obtain crude product, and purifying by high performance liquid chromatography (column type: XBRID PREP AMIDE OBD,19mm×150mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 25mL/min; gradient: 95% -50% acetonitrile 8min; wavelength: 254/220 nm) to obtain 4- (dimethylamino) but-2-ynoic acid (yellow oil, 100mg, 16.4%). MS (ESI ⁺)m/z＝128.3[M+H]⁺).

Preparation of intermediate C4.3- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) propionic acid

2-Acetyly pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg,2.56 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to-78℃and n-butyllithium (196.8 mg,3.07 mmol) was slowly added, stirred at-78℃for 1h, then dry ice was added and stirring continued for 2h. The reaction was quenched by the addition of water (10 mL) and concentrated under reduced pressure to give 3- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) propionic acid (white solid, 650mg, crude). MS (ESI ⁺)m/z＝240.2[M+H]⁺).

Preparation of intermediate C5-C6

The intermediate C5-C6 is prepared by taking a commercial alkynyl compound as a raw material and adopting an intermediate C4 synthesis method. As shown in table 3.

TABLE 3 intermediates C5-C6

Fourth group of preparation examples, preparation of intermediates D1-D3

Preparation of intermediate D1- (2- ((4-aminopyrimidin-5-yl) oxy) ethyl) (methyl) carbamic acid tert-butyl ester

First step 2- ((tert-Butoxycarbonyl) (methyl) amino) ethyl methane sulfonate

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

Second step (2- ((4-aminopyrimidin-5-yl) oxy) ethyl) (methyl) carbamic acid tert-butyl ester

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

Preparation of intermediate D2- (3- (4-aminopyrimidin-5-yl) oxy) cyclopentyl) carbamic acid tert-butyl ester

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

Preparation of intermediate D3.3- (((4-aminopyrimidin-5-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 3- (iodomethyl) pyrrolidine-1-carboxylate (1 g,3.4 mmol) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (1.3 g,10.2 mmol) and 4-aminopyrimidin-5-ol (541.0 mg,3.4 mmol) were added, and the mixture was warmed to 100℃and stirred for 1h. Cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using petroleum ether/ethyl acetate=0-76% as eluent to give 3- (((4-aminopyrimidin-5-yl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (yellow solid, 0.9g, 81.9%). MS (ESI ⁺)m/z＝295.1[M+H]⁺. Preparation of fifth group: preparation of intermediates E1-E11

Preparation of intermediate E1.2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid methyl ester

First step 4-chloropyrimidine-5-carboxylic acid ethyl ester

A solution of thionyl chloride (20 mL) in 4-hydroxypyrimidine-5-carboxylic acid ethyl ester (5.0 g,29.7 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise, and the mixture was stirred at 65℃for 16h. Cooled to room temperature and concentrated under reduced pressure to give ethyl 4-chloropyrimidine-5-carboxylate (pale yellow solid, 6.0g, 91.9%). MS (ESI ⁺)m/z＝187.0[M+H]⁺).

Second step 4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylic acid ethyl ester

3-Methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) aniline (500 mg,2.0 mmol) was dissolved in toluene (10 mL), 2-dicyclohexyl-2' - (N, N-dimethylamine) -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 4-chloropyrimidine-5-carboxylic acid ethyl ester (552.5 mg,3.0 mmol) were added sequentially, nitrogen was replaced, and the mixture was heated to 100℃and stirred for 2H. The mixture was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (100 mL. Times.3), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol/dichloromethane=0-10% as eluent to give ethyl 4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylate (yellow solid, 450mg, 50.9%). MS (ESI ⁺)m/z＝404.1[M+H]⁺).

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

Ethyl 4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylate (400 mg,1.0 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL) at 0℃and a solution of lithium hydroxide (119 mg,5.0 mmol) in water (5 mL) was added and stirred at room temperature for 2H. And adding 1N hydrochloric acid to adjust the pH to be 2-4, extracting the mixed solution with dichloromethane/methanol to be 10/1 (50 mL multiplied by 3), combining organic phases, drying the combined organic phases with anhydrous sodium sulfate, filtering the combined organic phases, and concentrating the filtrate under reduced pressure. The residue was purified by reverse phase column chromatography (column: C18 column, mobile phase: water and acetonitrile, 20% -30%10min, wavelength: 254 nm) to give 4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylic acid (yellow solid, 270mg, 65.3%). MS (ESI ⁺)m/z＝376.1[M+H]⁺).

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

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), N, N-diisopropylethylamine (946.9 mg,7.5 mmol), methyl 2-amino-3-hydroxypropionate hydrochloride (683.8 mg,4.5 mmol) and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (HBTU, 1.1g,3.0 mmol) were added sequentially and stirred at room temperature for 2H. The combined organic phases were washed with saturated sodium chloride solution (30 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol/dichloromethane=10% as eluent to give methyl (4- ((3-methyl-4- ((1-methyl-1H-benzoimidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carbonyl) serine (yellow solid, 470mg, 60.6%). MS (ESI ⁺)m/z＝477.2[M+H]⁺).

Fifth step 2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -4, 5-dihydro-oxazole-4-carboxylic acid methyl ester

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

Sixth step methyl 2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylate

2- (4- ((3-Methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -4, 5-dihydro-oxazole-4-carboxylic acid methyl ester (110 mg,0.2 mmol) was dissolved in dichloromethane (4 mL) under nitrogen, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 73.1mg,0.4 mmol) and trichlorobromomethane (95.1 mg,0.4 mmol) were added at-78℃and stirred for 2H at room temperature. The reaction was quenched with water (20 mL), extracted with dichloromethane/methanol=10/1 (30 ml×3), the combined organic phases were washed with saturated sodium chloride solution (30 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated and purified by silica gel chromatography using methanol/dichloromethane=10% as eluent to give methyl 2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylate (yellow solid, 70mg, 57.5%). MS (ESI ⁺)m/z＝457.2[M+H]⁺).

Preparation of intermediate E2.2- (4- ((3-methyl-4- (([ 1,2,4] triazolo [1,5-a ] pyridin-7-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid methyl ester

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 starting from 3-methyl-4- (([ 1,2,4] triazolo [1,5-a ] pyridin-7-yl) oxy) aniline and 4-chloropyrimidine-5-carboxylate. MS (ESI ⁺)m/z＝444.6[M+H]⁺).

Preparation of intermediate E3.2- (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

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

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) under nitrogen, N-diisopropylethylamine (5.2 g,40 mmol) and ethyl 7-chloropyrazolo [1,5-a ] pyrimidine-6-carboxylate (3 g,13.3 mmol) were added and the temperature was raised to 80℃and stirred for 2H. Cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography using methanol/dichloromethane=20% as eluent to give ethyl 7- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) aminopyrazolo [1,5-a ] pyrimidine-6-carboxylate (off-white solid, 5 g). MS (ESI ⁺)m/z＝443.1[M+H]⁺.

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

Ethyl 7- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) aminopyrazolo [1,5-a ] pyrimidine-6-carboxylate (2 g,4.5 mmol) was dissolved in ethanol (20 mL) and water (20 mL), sodium hydroxide (552 mg,13.6 mmol) was added, warmed to 50 ℃ and stirred for 8H, cooled to room temperature, 1N hydrochloric acid was added to adjust pH = 2-4, concentrated under reduced pressure to remove most of the solvent, white solid precipitated, filtered, the filter residue was washed with ice water and dried to give 7- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrazolo [1,5-a ] pyrimidine-6-carboxylate (white solid, 1.6 g) MS (ESI ⁺)m/z＝415.1[M+H]⁺).

Third step (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 ℃, and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (HATU, 3.3g,8.7 mmol) was added and stirred at room temperature for 2H. Concentrating under reduced pressure. The residue was purified by chromatography on silica gel to give methyl (7- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrazolo [1,5-a ] pyrimidine-6-carbonyl) serine (yellow solid, 1.8 g). MS (ESI ⁺)m/z＝516.2[M+H]⁺).

Fourth step 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

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

Fifth step 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

Methyl 2- (7- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrazolo [1,5-a ] pyrimidin-6-yl) -4, 5-dihydro-oxazole-4-carboxylate (as a starting 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 synthesis intermediate E1. MS (ESI ⁺)m/z＝496.1[M+H]⁺).

Preparation of intermediate E4.5-methyl-2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid methyl ester

5- ((4- ((5-Iodopyrimidin-4-yl) amino) -2-methylphenyl) oxy) -1-methyl-1H-benzimidazole (intermediate A2,1g,2.2 mmol) was dissolved in 1, 4-dioxane (20 mL) under nitrogen, 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-methyl-oxazole-4-carboxylate (617.2 mg,4.4 mmol) were added sequentially and the mixture was warmed to 110℃and stirred for 36H. Cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol/dichloromethane=10% as eluent to give methyl 5-methyl-2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylate (pale yellow solid, 200mg, 19.0%). MS (ESI ⁺)m/z＝471.0[M+H]⁺).

Preparation of intermediate E5.2- (4-methyl-6- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid ethyl ester

Starting from intermediate A9 and ethyl oxazole-4-carboxylate, 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, 239mg, 23%) was prepared according to the synthetic method of intermediate E4. MS (ESI ⁺)m/z＝485.2[M+H]⁺).

Preparation of intermediate E6.2- (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

In the first step, intermediate A25 (1.4 g,3.42 mmol) was dissolved in DMF (30 mL), DIEA (1.3 g,10.25 mmol) and methyl 2-amino-3-hydroxypropionate (610.4 mg,5.12 mmol) were added sequentially, cooled to 0deg.C, and HATU (2.6 g,6.8 mmol) in DMF (5 mL) was added slowly. The mixture was warmed to room temperature and stirred for 1h. After completion of the reaction, water (50 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane/methanol (10/1 v/v,60 mL. Times.3), the combined organic phases were washed with saturated sodium chloride solution (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by column chromatography on silica gel eluting with methanol/dichloromethane (1/10) to give methyl (4-chloro-6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carbonyl) serine (yellow solid, 1.3g, 75.0%). MS (ESI ⁺)m/z＝511.3[M+H]⁺).

In a second step, (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) was dissolved in isopropanol (50 mL) and p-methoxybenzylamine (563.8 mg,4.11 mmol) was added. The temperature is raised to 60 ℃ and stirred for 2 hours. After the reaction was completed, cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography eluting with methanol/dichloromethane (1/10) as an eluent to give methyl (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carbonyl) serine (pale yellow solid, 1.3g, 81.0%). MS (ESI ⁺)m/z＝612.4[M+H]⁺).

The third and fourth steps were carried out starting from methyl (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) (620 mg, 57.0%) of 2- (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-4-carboxylate (as a pale yellow solid according to the fifth and sixth steps of the synthetic intermediate E1. MS (ESI ⁺)m/z＝592.3[M+H]⁺).

Preparation of intermediate E7.2- (4- ((2-fluoro-3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid ethyl ester

In the first step, 5-bromo-4-chloropyrimidine (10.0 g,51.70 mmol) was dissolved in N, N-dimethylformamide (100 mL), and sodium methyl mercaptide (4.3 g,62.04 mmol) was added. Stirring at room temperature for 12h. After completion of the reaction, water (100 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (200 ml×3), the combined organic phases were washed with saturated sodium chloride solution (200 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (40%) as an eluent to give 5-bromo-4- (methylthio) pyrimidine (pale yellow oil, 6g, 56.6%). MS (ESI ⁺)m/z＝207.0[M+H]⁺).

In a second step, 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), dipicolinate (18.6 g,73.15 mmol) and potassium acetate (12.0 g,121.91 mmol) were added sequentially under nitrogen. The temperature was raised to 90 ℃ and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, water (100 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were washed with saturated sodium chloride solution (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-methylthio-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (brown solid, 6g, crude). MS (ESI ⁺)m/z＝253.3[M+H]⁺).

In the third step, 4-methylthio-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (6.0 g,23.80 mmol) was dissolved in a mixture of 1, 4-dioxan and water (4/1 v/v,62.5 mL), and Xphos Pd G (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) were added sequentially under nitrogen. The temperature is raised to 80 ℃ and stirred for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (100 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 ml×3), the combined organic phases were washed with saturated sodium chloride solution (100 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (50%) as eluent to give ethyl 2- (4- (methylthio) pyrimidin-5-yl) oxazole-4-carboxylate (pale yellow solid, 2g, 31.7%). MS (ESI ⁺)m/z＝266.0[M+H]⁺).

In a fourth step, ethyl 2- (4- (methylthio) pyrimidin-5-yl) oxazole-4-carboxylate (1.1 g,4.15 mmol) was dissolved in dichloromethane (15 mL), cooled to 0deg.C and sulfonyl chloride (1.1 g,8.29 mmol) was added. Stirred at 0 ℃ for 0.5h. After the reaction was completed, the reaction mixture was warmed to room temperature and concentrated under reduced pressure, and the obtained residue was eluted with petroleum ether (100%) as an eluent to obtain ethyl 2- (4-chloropyrimidin-5-yl) oxazole-4-carboxylate (pink solid, 1.2g, crude product). MS (ESI ⁺)m/z＝254.0[M+H]⁺).

Fifth step ethyl 2- (4-chloropyrimidin-5-yl) oxazole-4-carboxylate (473.4 mg,1.87 mmol) was dissolved in isopropanol (20 mL) and intermediate F4 (359.5 mg,1.33 mmol) was added. The temperature is raised to 90 ℃ and stirred for 1h. After the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography eluting with methanol/dichloromethane (1/10) as an eluent to give 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, 625mg, 68.5%). MS (ESI ⁺)m/z＝489.3[M+H]⁺).

Preparation of intermediates E8-E10.

The intermediate E8-E10 is prepared by taking 2- (4-chloropyrimidine-5-yl) oxazole-4-ethyl formate or 2- (4-chloropyrimidine-5-yl) oxazole-4-methyl formate and intermediates F1-F9 as raw materials according to a method for synthesizing the intermediate E7. As shown in table 4.

TABLE 4 intermediates E8-E10

Preparation of intermediate E11.2- (4- ((3-chloro-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid ethyl ester

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

Second step 2- (4- ((3-chloro-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylic acid ester (intermediate E11, yellow solid, 180mg, 12.0%) was prepared according to the fifth step method of synthesis intermediate E7 starting from ethyl 2- (4- (methylsulfonyl) pyrimidin-5-yl) carboxylate (200 mg,2.24 mmol) and 3-chloro-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) aniline (intermediate F6). MS (ESI ⁺)m/z＝491.2[M+H]⁺).

Sixth group of preparation examples, preparation of intermediates F1-F9

Preparation of intermediates F1-F7.

The intermediate F1-F7 is prepared by using commercially available 1-methyl-1H-benzimidazol-5-ol and substituted nitrobenzene compounds as raw materials and adopting a first step and a second step of the intermediate A1. As shown in table 5.

TABLE 5 intermediates F1-F7

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

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

In the second step, 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 sequentially, and the mixture was warmed to 60℃and stirred for 1h, cooling to room temperature after completion of the reaction, water (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated by column chromatography on silica gel eluting with a gradient of ethyl acetate/petroleum ether (0-100%) to give 4-bromo-6-fluoro-N ¹ -methyl-1, 2-phenylenediamine (brown oil, 1.1g, 69.5%). MS (ESI ⁺)m/z＝219.0[M+H]⁺).

In the third step, 4-bromo-6-fluoro-N ¹ -methyl-1, 2-phenylenediamine (1.1 g,5.02 mmol) was dissolved in toluene (20 mL) under nitrogen, cooled to 0℃and p-toluenesulfonamide (86.0 mg,0.50 mmol) and triethylorthoformate (1.5 g,10.04 mmol) were added sequentially. The temperature is raised to 120 ℃ and stirred for 16h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added thereto, the mixture was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography using a gradient elution with ethyl acetate/petroleum ether (0-10%) as an eluent to give 5-bromo-7-fluoro-1-methyl-1H-benzo [ d ] imidazole (brown solid, 1.1g, 95.6%). MS (ESI ⁺)m/z＝228.9[M+H]⁺).

In the fourth step, 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) under nitrogen, cu (acac) ₂ (114.3 mg,0.44 mmol) and BHMPO (143.4 mg,0.44 mmol) were added sequentially, followed by slow addition of lithium hydroxide monohydrate (769.4 mg,18.34 mmol). The temperature is raised to 80 ℃ and stirred for 2h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added thereto, the mixture was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography eluting with a gradient of methanol/dichloromethane (0-20%) as an eluent to give 7-fluoro-1-methyl-1H-benzo [ d ] imidazol-5-ol (light brown solid, 650mg, 89.7%). MS (ESI ⁺)m/z＝167.1[M+H]⁺).

The fifth and sixth steps were prepared 3-chloro-4- ((7-fluoro-1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) aniline (yellow solid 450mg, 90.2%) according to the first and second steps of intermediate A1 starting from 7-fluoro-1-methyl-1H-benzo [ d ] imidazol-5-ol and 2-chloro-1-fluoro-4-nitrobenzene. MS (ESI ⁺)m/z＝291.9[M+H]⁺).

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

In the first step, 7-chloroimidazo [1,2-c ] pyrimidine (500.0 mg,3.26 mmol) was dissolved in acetonitrile (8 mL) under nitrogen, and potassium carbonate (900.0 mg,6.51 mmol) and 2-methyl-4-nitrophenol (598.3 mg,3.91 mmol) were added. The temperature is raised to 80 ℃ and stirred for 2h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (20 mL) was added thereto, the mixture was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography using a gradient of ethyl acetate/petroleum ether (0-33%) as an eluent to give 7- (2-methyl-4-nitrophenoxy) imidazo [1,2-c ] pyrimidine (yellow solid, 180mg, 20.4%). MS (ESI ⁺)m/z＝271.1[M+H]⁺).

In the second step, 7- (2-methyl-4-nitrophenoxy) imidazo [1,2-c ] pyrimidine (170.0 mg,0.63 mmol) was dissolved in a methanol and water mixture (3/1 v/v,4 mL), and iron powder (281.1 mg,5.03 mmol) and ammonium chloride (269.2 mg,5.03 mmol) were added sequentially. The temperature is raised to 80 ℃ and stirred for 2h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography using methanol/dichloromethane (0-18%) as eluent to give 4- (imidazo [1,2-c ] pyrimidin-7-yloxy) -3-methylaniline (yellow solid, 120mg, 79.4%). MS (ESI ⁺)m/z＝241.0[M+H]⁺).

Seventh group of preparation examples: preparation of intermediate G1

Preparation of intermediate G1 (1- ((4-chloropyrimidin-5-yl) ethynyl) cyclopropyl) carbamic acid tert-butyl ester

4-Chloro-5-iodopyrimidine (1.0 g,4.16 mmol) was dissolved in N, N-dimethylformamide (10 mL), pd (PPh ₃)₂Cl₂ (291.9 mg,0.42 mmol), cuprous iodide (79.2 mg,0.42 mmol), triethylamine (4.2 g,41.59 mmol) and tert-butyl N- (1-ethynyl cyclopropyl) carbamate (753.8 mg,4.16 mmol) were added sequentially, and after the reaction was completed, cooled to room temperature, water (60 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40 mL. Times.3), the combined organic phases were washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography using ethyl acetate/petroleum ether (0-50%) as eluent gradient to give (yellow solid, 1.2g, 98.2%). MS (ESI ⁺)m/z＝294.1[M+H]⁺).

Eighth group of preparation examples, preparation of end product

Example 1.1 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 (end product 1)

First step 2- ((4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) azetidine-1-carboxylic acid tert-butyl ester

5- ((4- ((5-Bromopyrimidin-4-yl) amino) -2-methylphenyl) oxy) -1-methyl-1H-benzimidazole (intermediate A3,200mg,0.5 mmol) was dissolved in N, N-dimethylformamide (10 mL), tert-butyl 2-ethynyl azetidine-1-carboxylate (intermediate B1,457.4mg,2.5 mmol), cuprous iodide (1.0 mg,0.005 mmol), ditolylphosphine palladium dichloride (35.4 mg,0.05 mmol) and triethylamine (1.15 g,1.5 mmol) were added sequentially under nitrogen, and stirred for 1H at 100 ℃. Cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether=0-50% as eluent to give 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, 180mg, 35.8%). MS (ESI ⁺)m/z＝511.4[M+H]⁺).

Second step 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 stirred at room temperature for 1H. The reaction was quenched with water (20 mL), the mixture was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 5- (azetidin-2-ylethynyl) -N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (yellow liquid, 80mg,39.9%, crude product). MS (ESI ⁺)m/z＝411.2[M+H]⁺).

Third step 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℃and acrylic anhydride (22.1 mg,0.2 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 1H. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by high pressure reverse flow preparative chromatography (column: XSelect CSH Fluoro Phenyl,19mm x 250mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 60mL/min; gradient: 50% -75% acetonitrile 7min; wavelength: 254 nm) to give 1- (2- ((4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) azetidin-1-en-1-one.

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

The condensation method further comprises the steps of 1) taking a commercial alkene/alkynoic acid compound or an intermediate C1-C6 as a raw material, EDCI as a catalyst and pyridine as a solvent to react at room temperature, and 2) taking alkene/alkynoic acid compound as a raw material, triethylamine as a catalyst and THF as a solvent to react at room temperature.

Examples 2-75 preparation of end product 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

Using the method of preparation of end product 1, end product 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, is prepared starting from intermediates A1-A28, intermediates B1-B22, intermediates C1-C6 or commercially available alkynyl compounds and commercially available other compounds as shown in Table 6.

TABLE 6 end product 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 preparation of (R, Z) -2-fluoro-N- (3- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) propyl-2-yn-1-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide and (R, E) -2-fluoro-N- (3- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) propyl-2-yn-1-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide (final product 30)

First step (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-alkynyl-1-yl) amino) -3-oxopropyl-1-en-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

5- (3-Aminopropyl-1-alkynyl) -N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (prepared according to the procedure of the first and second steps in example 1 starting from intermediate A3) (120 mg,0.3 mmol) was dissolved in pyridine (14 mL), (R) -3- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -2-fluoroprop-2-enoic acid (121.4 mg,0.45 mmol) was added, the mixture was cooled to 0℃and phosphorus oxychloride (95.7 mg,0.6 mmol) was added dropwise and stirred for 1H at 0 ℃. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was isolated and purified by silica gel chromatography using methanol/dichloromethane=0-20% as eluent to give (R, Z/E) -2- (2-fluoro-3- ((3- (4- ((3-methyl-4- ((1-methyl-1H-benzoimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) propyl-2-alkynyl-1-yl) amino) -3-oxoprop-1-en-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 35.0%). MS (ESI ⁺)m/z＝626.5[M+H]⁺).

Second step (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-alkynyl-1-yl) -3- (pyrrolidin-2-yl) acrylamide

(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-alkynyl-1-yl) amino) -3-oxopropyl-1-en-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg,0.09 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1.2 mL) was added and stirred at room temperature for 1H. Concentration under reduced pressure afforded (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, 66mg, crude). MS (ESI ⁺)m/z＝526.4[M+H]⁺).

Third step (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), aqueous formaldehyde (37 wt%,90mg,1.14 mmol) was added, stirred at room temperature for 1H, sodium triacetoxyborohydride (120.9 mg,0.5 mmol) was added in portions, and stirred at room temperature for 4H. The reaction was quenched with sodium bicarbonate solution (20 mL), extracted with dichloromethane (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated and purified by Column chromatography (Column: xselect CSH C OBD Column,30 mm. Times.150 mm,5 μm; mobile phase: water (0.1% formic acid)/acetonitrile; flow rate: 60mL/min; gradient: 5% -20% acetonitrile 10min; wavelength: 254/220 nm) to give (R, Z) -2-fluoro-N- (3- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-5-yl) propyl-2-yn-1-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide (end product 30A) and (R, E) -2-fluoro-N- (3- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -3- (1-methylpyrrolidin-2-yl) acrylamide (end product 30B). The end products 30A and 30B are not identified as specifically corresponding to either the cis (Z) configuration or the trans configuration (E).

End product 30A

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

End product 30B

Off-white solid ,MS(ESI⁺)m/z＝540.2[M+H]⁺.¹H NMR(500MHz,CD₃OD)δ8.55(s,1H),8.31(s,1H),8.14(d,J＝2.5Hz,1H),7.73(s,1H),7.63(d,J＝8.7Hz,1H),7.57(d,J＝8.4Hz,1H),7.24-7.11(m,2H),6.95(d,J＝8.7Hz,1H),5.91-5.83(m,1H),4.78-4.60(m,1H),4.43(s,2H),3.98(s,3H),3.56-3.43(m,1H),2.82-2.69(m,1H),2.69-2.57(m,3H),2.38(s,3H),2.30(s,1H),2.01(d,J＝32.8Hz,2H),1.81(s,1H).

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 (end 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 according to the procedure for the synthesis of end product 30 starting from N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-oxy) phenyl) -5- (piperidin-2-ylethynyl) pyrimidin-4-amine.

White solid ,MS(ESI⁺)m/z＝594.2[M+H]⁺.¹H NMR(500MHz,CDCl₃)δ8.68(s,1H),8.42(s,2H),7.89(s,1H),7.63-7.22(m,4H),7.11-7.03(m,1H),6.88(d,J＝8.7Hz,1H),5.91-5.54(m,2H),3.87(s,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-morpholinbut-2-enamide (final product 33)

First step (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 according to the procedure of the first and second steps of example 1 starting from intermediate A2) (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 1H. Concentration under reduced pressure afforded (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 (brown oil, 400mg, crude). MS (ESI ⁺)m/z＝557.3[M+H]⁺).

Second step (2E) -N- (1- ((4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) cyclopropyl) -4-morpholinbut-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 (447 mg,0.8 mmol) was dissolved in acetonitrile (4 mL), morpholine (104.5 mg,1.2 mmol), potassium carbonate (331.7 mg,2.4 mmol) was added sequentially, nitrogen was replaced, and the temperature was raised to 60℃and stirred for 3H. Cooling to room temperature, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by high pressure chromatography (column: YMC-Actus Triart C18: 18ExRS, 30X 150mm; mobile phase: water (10 mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 60mL/min; gradient: 26% -46% acetonitrile 10min; wavelength: 254/220 nm) to give (2E) -N- (1- ((4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) cyclopropyl) -4-morpholinbut-2-enamide.

White solid ,MS(ESI⁺)m/z＝564.4[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ8.96(s,1H),8.66(s,1H),8.55(s,1H),8.30(s,1H),8.17(s,1H),7.80(s,1H),7.72-7.64(m,1H),7.56(d,J＝8.7Hz,1H),7.09(d,J＝2.2Hz,1H),7.03-6.95(m,1H),6.84(d,J＝8.7Hz,1H),6.75-6.62(m,1H),6.05(d,J＝15.6Hz,1H),3.84(s,3H),3.49(t,J＝4.6Hz,4H),3.09-3.00(m,2H),2.33-2.21(m,7H),1.41-1.26(m,2H),1.26-1.11(m,2H).

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)

First step 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

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

Second step 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), and triethylamine (171.9 mg,1.2 mmol) was added and stirred at room temperature for 1H. After the completion of the reaction, the reaction was quenched with water (5 mL), extracted with ethyl acetate (30 mL. Times.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 high pressure chromatography (Column: XBridge Prep OBD C Columbn, 30 mm. Times.150 mm,5 μm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 33% -47% acetonitrile 10min; wavelength: 254/220 nm) to give 1- (2- ((4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) piperidin-2-yn-1-one.

Pale yellow solid ,MS(ESI⁺)m/z＝491.3[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ8.74(s,1H),8.49(d,J＝13.8Hz,2H),8.17(s,1H),7.56(d,J＝8.7Hz,1H),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-yn-namide (final product 58)

In the first step, 3-chloro-2-fluoro-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) aniline (intermediate F2,200.0mg,0.69 mmol) was dissolved in t-butanol (5 mL), and tert-butyl (1- ((4-chloropyrimidin-5-yl) ethynyl) cyclopropyl) carbamate (intermediate G1,201.4mg,0.69 mmol), hydrochloric acid and 1, 4-dioxane mixture (25.0 mg,0.69 mmol) were added sequentially. The temperature is raised to 70 ℃ and stirred for 1h. After the reaction was completed, cooled to room temperature, the reaction solution was concentrated under reduced pressure, the pH was adjusted to be alkaline with sodium bicarbonate solution, the mixture was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by column chromatography on silica gel eluting with methanol/dichloromethane (0-15%) as an eluent to give tert-butyl (1- ((4- ((3-chloro-2-fluoro-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) cyclopropyl) carbamate (pale yellow solid, 150mg, 39.9%). MS (ESI ⁺)m/z＝549.1[M+H]⁺).

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

In a third step, 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) was dissolved in pyridine (5 mL) and EDCI (176.8 mg,0.92 mmol) and 2-butynoic acid (19.4 mg,0.23 mmol) were added sequentially. Stirring at room temperature for 0.5h. After completion of the reaction, water (30 mL) was added to the reaction mixture, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high pressure liquid chromatography (Column: kinetex EVO C Columbn, 21.2X105 mm,5 μm; mobile phase: acetonitrile/water (10 mmol/L ammonium bicarbonate); flow rate: 60mL/min; gradient: 28-53-11min; wavelength: 254/220 nm) to give 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]⁺.¹H NMR(300MHz,DMSO-d₆)δ9.25(s,1H),8.59(s,1H),8.47(s,1H),8.35(s,1H),8.25(s,1H),7.66(d,J＝8.7Hz,1H),7.46(t,J＝8.9Hz,1H),7.35(d,J＝2.3Hz,1H),7.11(dd,J＝8.7,2.3Hz,1H),6.75(dd,J＝9.0,1.8Hz,1H),3.87(s,3H),1.96(s,3H),1.44-1.34(m,2H),1.19-1.08(m,2H).

Examples 81-83 preparation of end product 145,150,151

The end product 145,150,151 was prepared using the preparation of end product 58, starting from intermediates F1-F9, intermediate G1 or commercially available compounds. As shown in table 7.

TABLE 7 end product 145,150,151

Example 84.1 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 (end product 67)

First step 2- ((2-chloro-4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) pyrrolidine-1-carboxylic acid tert-butyl ester

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

Second step 2- ((2-amino-4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) pyrrolidine-1-carboxylic acid tert-butyl ester

2- ((2-Chloro-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl tert-butyl 2- ((2-chloro-4- ((1-methyl-1H-benzimidazol-5-yl) carboxylate (100 mg,0.18 mmol) was dissolved in ethanol/water mixed solution (4/1, 5 mL), 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 ℃ and stirred for 1H under nitrogen. Cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated and purified by silica gel chromatography using methanol/dichloromethane=0-20% as eluent to give tert-butyl 2- ((2-amino-4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) pyrrolidine-1-carboxylate (white solid, 96mg, 99.5%). MS (ESI ⁺)m/z＝540.3[M+H]⁺).

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

1- (2- ((2-Amino-4- ((3-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) pyrrolidin-2-en-1-one was prepared according to the second and third step synthetic methods of example 1 starting from tert-butyl 2- ((2-amino-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) pyrrolidin-1-carboxylate.

White solid ,MS(ESI⁺)m/z＝494.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)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)

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

Methyl 2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-4-carboxylate (60 mg,0.1 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to-78 ℃ and lithium aluminum hydride (10.0 mg,0.2 mmol) was added and warmed to room temperature and stirred for 3H. The reaction was quenched by addition of water (10 mL) at 0deg.C, the mixture was extracted with dichloromethane/methanol (10/1, 30 mL. Times.3), the combined organic phases were washed with saturated sodium chloride solution (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate 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, 60mg, 95.9%). MS (ESI ⁺)m/z＝429.1[M+H]⁺).

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

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

Third step 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, 0.0070 mmol) were added and the mixture was stirred for 2H at 60 ℃. Cooled to room temperature, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by thin layer chromatography using methanol/dichloromethane=10% as eluent to give 5- (4- (aminomethyl) oxazol-2-yl) -N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine (yellow oil, 23mg, 81.3%). MS (ESI ⁺)m/z＝428.2[M+H]⁺).

Fourth step N- ((2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

Starting from 5- (4- (aminomethyl) oxazol-2-yl) -N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) pyrimidin-4-amine and acrylic anhydride, 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 procedure of example 1.

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

Examples 86-95 preparation of end products 82,83,88-90,96,102,104,165-166

Using the method for preparing end product 81, end products 82,83,88-90,96,102,104,165-166 were prepared starting from intermediates E1-E11 as shown in Table 8.

TABLE 8 end 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)

First step (2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazol-4-yl) carbaldehyde

(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 ℃, and dess-martin oxidant (DMP, 959.9mg,2.33 mmol) was added. The reaction mixture was stirred at room temperature for 4h, and quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The organic phase was separated, 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]⁺).

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

To a 40mL reaction flask was added (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), cooled to 0 ℃, and a solution of dimethyl magnesium bromide (2M, 209.0mg,1.75 mmol) in tetrahydrofuran was added dropwise under nitrogen. The reaction was quenched by adding methanol (1 mL) and concentrated under reduced pressure, and the residue was purified by silica gel column with methanol/dichloromethane=0% -20% as eluent to give (2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazol-4-yl) ethanol (284.0 mg, 73%) as a pale yellow solid. MS (ESI ⁺)m/z＝443[M+H]⁺).

The third, fourth and fifth steps are 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

Starting from (2- (4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazol-4-yl) ethanol, N- (1- (2- (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]⁺.¹H NMR(300MHz,DMSO-d₆)δ10.91(s,1H),8.95(s,1H),8.73(s,1H),8.59(d,J＝8.2Hz,1H),8.23(s,1H),8.17(s,1H),7.70-7.60(m,2H),7.57(d,J＝8.7Hz,1H),7.08(d,J＝2.3Hz,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 (end product 107)

In the first step, (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) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, dess-Martin reagent (1.1 g,2.66 mmol) was added and stirred for 1H at 0 ℃. After completion of the reaction, saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture at 0 ℃ and the mixture was extracted with dichloromethane/methanol (10/1 v/v,20ml×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 concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography using methanol/dichloromethane (10%) as eluent to give 2- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxazole-carbaldehyde (yellow oil, 250mg, 66.1%). MS (ESI ⁺)m/z＝427.1[M+H]⁺).

In the second step, 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) under nitrogen, cooled to 0℃and tert-butylsulfinamide (85.3 mg,0.70 mmol) and tetraethyltitanate (267.5 mg,1.17 mmol) were added in sequence and stirred overnight at room temperature. After completion of the reaction, saturated sodium chloride solution (10 mL) was added to the reaction mixture, filtered, the filter cake was washed with methanol (20 ml×3), and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography eluting with methanol/dichloromethane (10%) to give 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-sulfinamide (yellow oil, 150mg, 48.3%). MS (ESI ⁺)m/z＝530.3[M+H]⁺).

And thirdly, dissolving 2-methyl-N- ((2- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-yl) methylene) propane-2-sulfinamide (150.0 mg,0.28 mmol) in tetrahydrofuran (2 mL) under the protection of nitrogen, cooling to-78 ℃, dropwise adding (1, 3-dioxane-2-ethyl) magnesium bromide (621.3 mg,2.83 mmol), and stirring at-78 ℃ for 1H. After completion of the reaction, saturated aqueous ammonium chloride (10 mL) was added to the reaction solution at-78 ℃ and warmed to room temperature, the mixture was extracted with ethyl acetate (10 ml×3), the combined organic phases were washed with saturated aqueous sodium chloride (10 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was isolated by eluting with an acetonitrile/water gradient (10% -50% -20 min) as eluent over a reverse phase C18 column 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-methylpropan-2-sulfinamide (white solid, 20mg, 10.9%). MS (ESI ⁺)m/z＝646.3[M+H]⁺).

Fourth step 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-methylpropan-2-sulfinamide (20.0 mg,0.031 mmol) was dissolved in trifluoroacetic acid and water mixture (1/1 v/v,1 mL) and stirred at room temperature for 1H. After completion of the reaction, 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, 15mg, crude). MS (ESI ⁺)m/z＝466.3[M+H]⁺).

Fifth step 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) was dissolved in a trifluoroacetic acid and water mixture (1/1 v/v,1 mL), cooled to-20℃and sodium triacetoxyborohydride (13.7 mg,0.064 mmol) was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture to adjust the pH to 8, the mixture was extracted with ethyl acetate (10 mL. Times.3), the combined organic phases were washed with saturated sodium chloride solution (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give N- (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) -5- (4- (pyrrolidin-2-yl) oxazol-2-yl) pyrimidin-4-amine (yellow oil, 15mg, crude). MS (ESI ⁺)m/z＝468.3[M+H]⁺).

Sixth step 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) was dissolved in tetrahydrofuran (1 mL), triethylamine (9.7 mg,0.10 mmol) was added, cooled to 0℃and acryloyl chloride (2.3 mg,0.026 mmol) was added dropwise and stirred at room temperature for 15min. After completion of the reaction, water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (10 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by high pressure liquid chromatography (Column: XBridge BEH Shield RP Column, 19X 250mm,5 μm; mobile phase: acetonitrile/water (10 mmol/L ammonium bicarbonate; flow rate: 25mL/min; gradient: 35-56-10min; 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-one (4 mg, 25.1%).

White solid ,MS(ESI⁺)m/z＝522.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.76(s,0.5H),10.60(s,0.5H),8.94(d,J＝3.8Hz,1H),8.73(s,1H),8.37-8.10(m,2H),7.78-7.47(m,3H),7.16-7.09(m,1H),7.00(dd,J＝8.7,2.3Hz,1H),6.89(dd,J＝8.7,2.0Hz,1H),6.72-6.61(m,1H),6.24-6.12(m,1H),5.74-5.56(m,1H),5.10-5.47(m,1H),3.84(s,3H),3.82-3.46(m,2H),2.34-2.22(m,4H),2.21-2.14(m,1H),2.13-2.05(m,1H),1.99-1.89(m,1H).

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 (end product 108)

In the first step, 3-amino-1- (t-butoxycarbonyl) piperidine-3-carboxylic acid (500 mg,2.05 mmol) was added to a 40mL bottle under nitrogen, cooled to-15 ℃, BH ₃. THF (1M, 5 mL) was slowly added dropwise, stirred at room temperature for 3h, methanol (10 mL) was slowly added dropwise after completion of the reaction until no bubbles were generated, the mixture was concentrated under reduced pressure, a small amount of ethyl acetate was added, then a hydrochloric acid ethyl acetate solution was slowly added dropwise to adjust pH to 5-6, concentrated under reduced pressure, the resulting residue was dissolved in dichloromethane/methanol (5 mL, 10/1), sodium bicarbonate solution (5 mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane/methanol (10/1 v/v,5 mL. Times.3), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (brown oil, 490mg, crude product). MS (ESI ⁺)m/z＝231.0[M+H]⁺).

In a second step, 4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylic acid (intermediate A26,815.0mg,2.17 mmol) was dissolved in N, N-dimethylformamide (5 mL), DIEA (420.9 mg,3.26 mmol) and HATU (1.2 g,3.26 mmol) were added in sequence and stirred at room temperature for 5min. (3-amino-1-Boc-3-piperidinyl) methanol (500.0 mg,2.17 mmol) was further added thereto and stirred at room temperature for 3 hours. After completion of the reaction, water (5 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (10 ml×3), the combined organic phases were washed with saturated sodium chloride solution (5 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was separated by column chromatography on silica gel eluting with a gradient of methanol/dichloromethane (0-15%) to give tert-butyl 3-hydroxymethyl-3- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) piperidine-1-carboxylate (yellow oil, 500mg, 39.2%). MS (ESI) ⁺)m/z＝588.3[M+H]⁺

Third step 3-hydroxymethyl-3- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) piperidine-1-carboxylic acid tert-butyl ester (470.0 mg,0.80 mmol) was dissolved in dichloromethane (6 mL), cooled to-78 ℃ and DAST (386.7 mg,2.40 mmol) was slowly added dropwise under nitrogen. The mixture was warmed to room temperature and stirred for 1h. After completion of the reaction, aqueous sodium hydrogencarbonate (10 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane (10 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was separated by basic silica gel column chromatography eluting with methanol/dichloromethane (0-8%) as an eluent gradient to give 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, 200mg, 43.9%). MS (ESI ⁺)m/z＝570.4[M+H]⁺).

Fourth step 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 (200.0 mg,0.35 mmol) was dissolved in dichloromethane (1 mL), cooled to 0deg.C, trifluoroacetic acid (1 mL) was added and stirred at room temperature for 0.5H. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 1- (2- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -3-oxa-1, 7-diazaspiro [4.5] dec-1-en-7-yl) prop-2-en-1-one (brown oil, 200mg, crude product). MS (ESI ⁺)m/z＝470.4[M+H]⁺).

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

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

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)

First step (3- (4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) phenyl) carbamic acid tert-butyl ester

To a 25mL reaction flask was added sequentially 5- ((4- ((5-iodopyrimidin-4-yl) amino) -2-methylphenyl) oxy) -1-methylbenzimidazole (intermediate A2,300mg,0.7 mmol), a 1, 4-dioxane/water mixture (5/1, 3 mL), 3- ((tert-butoxycarbonyl) amino) phenylboronic acid (233.3 mg,1 mmol), pd (PPh ₃)₄ (75.8 mg,0.07 mmol) and potassium carbonate (272 mg,2.0 mmol), displaced nitrogen, warmed to 90℃Cj and stirred for 1h, cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography column with methanol/dichloromethane=10% -15% as eluent to give (3- (4- ((3-methyl-benzimidazol-5-yl) oxy) phenyl) pyrimidin-5-yl) phenyl) carbamic acid as a yellow oil (MS ⁺)m/z＝523.4[M+H]⁺.3402.3402%.

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

N- (3- (4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) phenyl) acrylamide was prepared according to the synthesis methods of the second and third steps of example 1 starting from tert-butyl (3- (4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) phenyl) carbamate.

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

EXAMPLE 100N- (3- (2-amino-4- ((3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) phenyl) acrylamide (end product 112)

Starting from intermediate a11 and 3- ((tert-butoxycarbonyl) amino) phenylboronic acid, 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 end product 109.

White solid ,MS(ESI+)m/z＝492.1[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ10.15(s,1H),8.07(s,1H),7.77(s,1H),7.71-7.63(m,2H),7.60(s,1H),7.55-7.41(m,3H),7.33(t,J＝7.9Hz,1H),7.04(d,J＝2.3Hz,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)

To a 25mL single flask under nitrogen was added 5-bromo-6- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-4-amine (intermediate A10,200mg,0.5 mmol), a1, 4-dioxane/water mixture (10/1, 5.5 mL), 3- (prop-2-enamino) 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) in sequence, and the mixture was warmed to 90℃and stirred for 3h. Cooled to room temperature, the mixture was extracted with ethyl acetate (5 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high pressure chromatography (Column: XBridge Prep OBD C Columb, 30 mm. Times.150 mm,5 μm; mobile phase: water (10 mmol/L ammonium bicarbonate)/acetonitrile; flow rate: 60mL/min; gradient: 24% -54% acetonitrile 7min; wavelength: 254/220 nm) to give 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]⁺.¹H NMR(300MHz,DMSO-d₆)δ10.25(s,1H),8.14(s,1H),8.06(s,1H),7.89-7.79(m,1H),7.61-7.43(m,3H),7.37-7.26(m,2H),7.20(s,1H),7.08-6.97(m,2H),6.96-6.89(m,1H),6.78-6.69(m,1H),6.52-6.40(m,1H),6.31-6.22(m,1H),5.81-5.70(m,3H),3.82(s,3H),2.11(s,3H).

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)

Starting from intermediate a12 and 3- ((tert-butoxycarbonyl) amino) phenylboronic acid, 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 end product 110.

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

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 (end product 113)

First step 6- (4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester

5- ((4- ((5-Bromopyrimidin-4-yl) amino) -2-methylphenyl) oxy) -1-methylbenzimidazole (intermediate A3,340mg,0.8 mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl 2, 6-diazaspiro [3.3] heptane-2 carboxylate (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) (RuphosPdG, 74mg,0.09 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl gold (I) (XPhosAuCl, 84mg,0.16 mmol) was added sequentially, and the mixture was stirred for 1h at 90 ℃. Cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography using ethyl acetate/petroleum ether (0-50%) as eluent gradient to afford 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, 320mg, 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

1- (6- (4- ((3-Methyl-4- (1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -2, 6-diazaspiro [3.3] heptane-2-en-1-one was prepared according to the synthesis method of the second and third steps of example 1 starting from tert-butyl 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.

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

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

N- (7- (4- ((3-methyl-4- ((1-methylbenzimidazole-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) -7-azaspiro [3.5] nonan-2-yl) acrylamide is prepared according to the synthesis method of the final product 113 by using intermediate A3 and N- (7-azaspiro [3.5] non-2-yl) carbamic acid tert-butyl ester as raw materials and Pd-PEPSI-IHept-Cl as a catalyst.

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

Example 105 preparation of N-methyl-N- (2- (4- (3-methyl-4- (1-methylbenzimidazole-5-oxy) phenyl) amino) pyrimidin-5-yl) oxy) ethanamide (final product 115)

First step methyl (2- ((4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxy) ethyl) carbamic acid tert-butyl ester

5- (4-Iodo-2-methylphenoxy) -1-methyl-1H-benzimidazole (intermediate A16,271.5mg,0.8 mmol) was dissolved in 1, 4-dioxane (2 mL), tert-butyl (2- ((4-aminopyrimidin-5-yl) oxy) ethyl) (methyl) carbamate (intermediate D1,100mg,0.4 mmol), cuprous iodide (7.1 mg,0.04 mmol), N, N-dimethylethylenediamine (3.3 mg,0.04 mmol) and Cs ₂CO₃ (531 mg,1.6 mmol) were added sequentially under nitrogen, and the mixture was warmed to 90℃and stirred overnight. The reaction was quenched with ice water (5 mL), extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel chromatography using petroleum ether/ethyl acetate=50% as eluent to give tert-butyl methyl (2- ((4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxy) ethyl) carbamate (yellow oil, 100mg, 53.2%). MS (ESI ⁺)m/z＝505.2[M+H]⁺).

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

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 a 1, 4-dioxane solution (0.2 mL) of 4M hydrochloric acid was added dropwise thereto under nitrogen and stirred at room temperature for 2h. After the completion of the reaction, the reaction was quenched by addition of sodium hydrogencarbonate solution (5 mL), extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography using petroleum ether/ethyl acetate=50% as eluent to give 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]⁺).

Third step N-methyl-N- (2- (4- (3-methyl-4- (1-methylbenzimidazole-5-oxy) phenyl) amino) pyrimidin-5-yl) oxy) ethanamide

N-methyl-N- (2- (4- (3-methyl-4- (1-methylbenzimidazol-5-yloxy) phenyl) pyrimidin-5-yl) oxy) ethanamide was prepared according to the third synthesis procedure of example 1 starting from N- (3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) -5- (2-methylaminoethoxy) pyrimidin-4-amine and acrylic anhydride.

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

Examples 106-107 preparation of end product 117 and end product 118

Using the preparation of end product 115, end products 117 and 118 were prepared starting from intermediate A16 and intermediates D2-D3, as shown in Table 9.

Table 9 end 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 (end product 116)

First step, 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 A15,160mg,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), cesium carbonate (451.6 mg,1.5 mmol) was added and stirred at room temperature for 1h. At the end of the reaction, quench the reaction with water (10 mL), extract with ethyl acetate (30 mL. Times.3), backwash the combined organic phases three times with water (10 mL), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the crude product. The crude product was 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, 90mg, 36.8%).

Second and third steps 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 preparation

1- (2- (((4- ((3-Methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxy) methyl) pyrrolidin-1-en-1-one was prepared according to the synthesis methods of the second and third steps of example 1 starting from tert-butyl 2- (((4- ((3-methyl-4- ((1-methylbenzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) oxy) methyl) pyrrolidin-1-en-1-one.

White solid ,MS(ESI+)m/z＝493.1[M+H]⁺.¹H NMR(300MHz,CD₃OD)δ8.22(s,1H),8.10(s,1H),7.97(s,1H),7.76-7.71(m,1H),7.69-7.63(m,1H),7.61-7.46(m,1H),7.13-7.05(m,2H),6.88(d,J＝8.7Hz,1H),6.75-6.63(m,1H),6.42-6.32(m,1H),5.86-5.75(m,1H),4.81-4.69(m,1H),4.33-4.11(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 (end product 120)

Starting from intermediate a15 and tert-butyl 4-iodopiperidine-1-carboxylate, 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 method of preparation of end product 116.

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

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) propynyl amide (final product 164)

First step 2- (3- ((1- ((3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidin-4-amine and 3- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) propiolic acid (intermediate C4) were prepared starting from 5- ((1-aminocyclopropyl) ethynyl) -N- (3-methyl-4- ((1-methyl-1H-benzimidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) cyclopropyl) amino) -3-oxopropyl-1-yn-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester according to the method of the third step of synthesizing end product 58. MS (ESI ⁺)m/z＝632.3[M+H]⁺).

Secondly, 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) propynyl amide (yellow solid, 150mg, crude product) was prepared according to the method of the second step of synthesizing final product 1 starting from tert-butyl 2- (3- ((1- ((4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) ethynyl) cyclopropyl) -3- (pyrrolidin-2-yl) propynyl amide. MS (ESI ⁺)m/z＝532.3[M+H]⁺).

In the third step, 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) propynylamide (140.0 mg,0.26 mmol) was dissolved in methanol (3 mL) under nitrogen and cooled to 0℃and aqueous formaldehyde (11.9 mg,0.40 mmol) was slowly added dropwise followed by sodium cyanoborohydride (82.7 mg,1.32 mmol). The mixture was warmed to room temperature and stirred for 1h. After completion of the reaction, water (30 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high pressure liquid chromatography (Column: XBridge Prep OBD C Columb, 19X 250mm,5 μm; mobile phase: acetonitrile/water (10 mmol/L ammonium bicarbonate); flow rate: 25mL/min; gradient: 34-64-7min; wavelength: 254/220 nm) to give 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) propynylamide.

White solid ,MS(ESI⁺)m/z＝546.3[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ9.48(s,1H),8.55(s,1H),8.45(s,1H),8.33(s,1H),8.17(s,1H),7.69(d,J＝2.4Hz,1H),7.57(dd,J＝8.7,2.7Hz,2H),7.08(d,J＝2.3Hz,1H),6.99(dd,J＝8.7,2.3Hz,1H),6.85(d,J＝8.7Hz,1H),3.84(s,3H),3.32-3.26(m,1H),2.75-2.64(m,1H),2.40-2.29(m,1H),2.28(s,3H),2.23(s,3H),2.17-1.99(m,1H),1.86-1.63(m,3H),1.45-1.31(m,2H),1.23-1.14(m,2H).

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)

In the first step, 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) was dissolved in methanol (10 mL), methylamine (13.3 mg,0.43 mmol) was added and stirred at room temperature for 0.5H. NaBH ₃ CN (67.0 mg,1.07 mmol) was added and stirred at room temperature for 0.5h. After completion of the reaction, methylene chloride (30 mL) was added to the reaction mixture, the mixture was washed with water (30 ml×3), the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give N- (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) -5- (4- ((methylamino) methyl) oxazol-2-yl) pyrimidin-4-amine (yellow solid, 57mg, 60.5%). MS (ESI ⁺)m/z＝442.0[M+H]⁺).

In the second step, N-methyl-N- ((2- (4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidin-5-yl) oxazol-4-amine was prepared according to the method of the third step of example 1 starting with N- (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) 5- (4- ((methylamino) methyl) oxazol-2-yl) pyrimidin-4-amine (2 mg, 3.1%).

White solid ,MS(ESI⁺)m/z＝496.2[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ10.96(s,0.5H),10.65(s,0.5H),8.95(d,J＝3.5Hz,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 (end product 168)

The first, second and third steps were carried out by starting from 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) and preparing 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, 95mg, 77.2%) according to the final product 81 first, second and third steps. MS (ESI ⁺)m/z＝564.3[M+H]⁺).

Fourth step 5- (4- (aminomethyl) oxazol-2-yl) -N ⁴ - (4-methoxybenzyl) -N ⁶ - (3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) pyrimidine-4, 6-diamine (95.0 mg,0.17 mmol) was dissolved in a trifluoroacetic acid/water mixture (9/1 v/v,3 mL) and stirred at room temperature for 1H. After completion of the reaction, concentrated under reduced pressure, methanol/dichloromethane (1/10 v/v,20 mL) was added, 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 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, 62mg, 83.0%). MS (ESI ⁺)m/z＝443.3[M+H]⁺).

And fifthly, taking 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 a raw material, and preparing N- ((2- (4-amino-6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidin-5-yl) methyl) acrylamide according to a fourth step method of a final product 81.

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

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 (end product 169)

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 procedure for the synthesis of end product 108 starting from 4- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxylic acid.

White solid ,MS(ESI⁺)m/z＝510.2[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ11.21(s,1H),8.73(d,J＝4.9Hz,2H),8.23-8.16(m,1H),7.60-7.49(m,3H),7.08(d,J＝2.1Hz,1H),7.01-6.93(m,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 (end product 170)

In the first step, 3- (4-chloro-6- ((3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) -3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (light yellow solid, 4476 mg, 42.0%) was prepared according to the second step method of synthesizing final product 108 starting from intermediate A25 and (3-amino-1-Boc-3-piperidinyl) methanol. MS (ESI ⁺)m/z＝622.4[M+H]⁺).

Second step 3- (hydroxymethyl) -3- (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) piperidine-1-carboxylic acid tert-butyl ester (370 mg, 71.4%) was prepared as a second step in the synthesis of intermediate E6 starting from 3- (4-chloro-6- ((3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) tert-butyl ester (370 mg, 71.4%) as a pale yellow oil. MS (ESI ⁺)m/z＝723.5[M+H]⁺).

Third step 3- (hydroxymethyl) -3- (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4-) ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-carboxamide) piperidine-1-carboxylic acid tert-butyl ester as starting material 2- (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-yl) -3-oxa-1, 7-diazaspiro [4.5] dec-1-ene-7-carboxylic acid tert-butyl ester (light yellow oil, 180mg, 49.9%) was prepared according to the method of the third step of synthesis of end product 108. MS (ESI ⁺)m/z＝705.5[M+H]⁺).

In a 40mL sample bottle, 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-carboxylic acid tert-butyl ester (180 mg,0.26 mmol) was dissolved in a mixture of trifluoroacetic acid and water (4.4 mL,1/10 v/v), and the mixture was heated to 80℃and stirred for 1H. After completion of the reaction, 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 (as a pale yellow oil, 250mg, crude). MS (ESI ⁺)m/z＝485.3[M+H]⁺).

And fifthly, taking 2- (4- ((4-methoxybenzyl) amino) -6- ((3-methyl-4- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) phenyl) amino) pyrimidine-5-yl) -3-oxa-1, 7-diazaspiro [4.5] dec-1-ene-7-carboxylic acid tert-butyl ester as a raw material, and preparing the 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 according to a method of synthesizing a final product 1 in a third step.

White solid ,MS(ESI⁺)m/z＝539.4[M+H]⁺.¹H NMR(300MHz,DMSO-d₆)δ11.48(d,J＝47.1Hz,1H),8.16(s,1H),8.05(s,1H),7.55(d,J＝8.8Hz,2H),7.48-7.37(m,1H),7.37-7.09(m,2H),7.04(s,1H),7.01-6.87(m,1H),6.87-6.79(m,2H),6.05(t,J＝15.6Hz,1H),5.70-5.48(m,1H),4.27-4.04(m,3H),3.84(s,4H),3.53(d,J＝13.2Hz,1H),3.14(t,J＝9.0Hz,1H),2.20(d,J＝9.0Hz,3H),1.94-1.71(m,3H),1.66-1.50(m,1H).

Comparative Compound A

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

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

Experimental example 1 cell proliferation inhibition experiment

The CellTiter-Glo ^TM living cell detection kit adopts luciferase as a detection object, and the luciferase needs ATP to participate in the luminescence process. The CellTiter-Glo ^TM reagent is added into the cell culture medium, the luminescence value is measured, the optical signal is proportional to the ATP amount in the system, and the ATP is positively related to the number of living cells. Thus, by detecting the ATP content using CellTiter-Glo kit, the proliferation of cells can be detected.

The proliferation inhibition of the compounds prepared above in tumor cell lines HER2 775-776insYVMA Ba/F3 and SK-BR-3 was measured by Celltiter-Glo (CTG) method, and 50% inhibition concentration IC ₅₀ was calculated.

1. Design of experiment

Compounds were assayed on selected cells and vehicle controls were set to measure 9 total concentrations, 2 duplicate wells per concentration.

2. Reagent and consumable

3. Experimental procedure

3.1 Cell culture

A) All cells were cultured according to ATCC recommendations. Cells in the logarithmic growth phase were harvested by culture. Detecting the cell activity, and ensuring the cell activity to be more than 90%.

B) Cell culture medium RPMI1640,10% FBS,1% P/S. Cell concentrations were adjusted and 95 μl or 90 μl of cell suspension was added to 96-well plates, respectively.

C) The cell culture environment is cultured under the conditions of 37 ℃ and 5% CO ₂ and 95% humidity.

3.2 Dilution of drugs

A) Drug stock solution the drug was dissolved in DMSO to prepare a 10mM DMSO stock solution.

B) Drug storage drug DMSO stock solutions were all stored in a room temperature desiccator for short periods (up to 3 months). The remaining drug was stored for a longer period of time at-20 ℃.

C) A20X or 10X drug solution was prepared by adding 2. Mu.L of drug stock solution to 98. Mu.L or 198. Mu.L of cell culture medium.

3.3 Dosing

A) All drugs were diluted 3-fold starting at 1 μm concentration, 9 concentration gradients or 4-fold dilution, 8 concentration gradients.

B) Positive control was formulated as DMSO blank.

C) mu.L of 20 Xdrug solution or 10. Mu.L of 10 Xdrug was added to each well of a 96-well plate inoculated with cells, and 2 multiplex wells were set for each drug concentration.

D) Cells in the dosed 96-well plates were incubated for a further 72 hours at 37 ℃, 5% CO ₂, 95% humidity before CTG analysis.

3.4 End point reading board

A) The CTG reagent was thawed, 50. Mu.L of CTG solution was added to each well, and the mixture was shaken well.

B) The cell plates were left to stand at room temperature for 10min to stabilize the luminescence signal.

C) The fluorescence value is read by an enzyme-labeled instrument.

4. Data processing

The data were analyzed using GRAPHPAD PRISM 7.0.0 software, a non-linear S-curve regression was used to fit the data to a dose-response curve, and IC ₅₀ values were calculated therefrom.

Inhibition ratio (Inh%) =100- (RLU _{compounds of formula (I)}-RLU_{Blank space})/(RLU_Control-RLU_{Blank space}) ×100%.

5. Experimental results

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

TABLE 10 proliferation inhibitory Activity of Compounds against HER2 775_776insYVMA Ba/F3 cell lines and SK-BR-3 cell lines (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 lines (expressing HER2 exon 20 insertion mutation) and SK-BR-3 cell lines (HER 2 overexpression), and inhibit IC ₅₀ to nanomolar concentration.

EXAMPLE 2A 431 phosphorylation assay

Cell culture

B) Cell culture medium DMEM,10%FBS,1%Glutamax and 1% P/S. Cell concentrations were adjusted, 40. Mu.L of cell suspension was added to 384 well plates, centrifuged at 1000rpm for 30s, and incubated for 4 hours.

C) The medium was removed, 25. Mu.L of HBSS was added to 384-well plates, and left overnight.

3.2 Dilution of drugs

3.3 Dosing

A) All drugs were diluted 3-fold starting at 10mM concentration, 10 concentration gradients.

B) Cells in 384 well plates were incubated for an additional 30min at 37℃with 5% CO ₂ and 95% humidity.

3.4 Detection

A) EGF was added as an activator and stimulated for 15min.

B) Cell lysates were prepared and tested according to the manufacturer's protocol.

C) The AlphaScreen is read by Envision.

4. Data processing

The data were analyzed using GRAPHPAD PRISM 8.0.0 software, a non-linear S-curve regression was used to fit the data to a dose-response curve, and IC ₅₀ values were calculated therefrom.

Inhibition rate (Inh%) =100- (Signal _{compounds of formula (I)}-Signal_{Ave_PC})/(Signal_{Ave_VC}-Signal_{Ave_PC}) 100%.

Signal _{Ave_PC} mean value of the Signal of the positive control over the whole plate

Signal _{Ave_VC} average value of signals of whole plate negative control

TABLE 11 Compounds inhibit EGFR phosphorylation pEGFR (IC ₅₀ nM) of the A431 cell line

End product numbering	A431pEGFR
		25	1216

As can be seen from the table, the compounds of the invention have an IC ₅₀ value of >1 mu M for inhibiting EGFR phosphorylation of A431 cell line, which shows that the compounds of the invention have weak inhibition on wild type EGFR and good selectivity on wild type EGFR.

Example 3:P-evaluation of gp substrate experiments

1. Test design

Cell culture

1) 10% Fetal bovine serum, 0.1mg/mL streptomycin and 0.6. Mu.g/mL were added using high glucose DMEM medium containing L-glutamine

Penicillin.

2) MDCKII-MDR1 was cultured in T-75 cell culture flasks. The incubator was set at 37 ℃, 5% CO ₂, ensuring a relative humidity of 95%.

The cell confluence reaches 70-90% and can be used for inoculation of Transwell.

3) Before cell seeding, 50. Mu.L of cell culture medium was added to each well of the Transwell upper chamber, and 25mL of cell culture medium was added to the lower plate. The plates were placed at 37℃and incubated in a 5% CO ₂ incubator for 1 hour before being used to inoculate cells.

4) Cells were gently washed with 5mL PBS. PBS was discarded, 1.5mL of pancreatin containing EDTA was added and incubated at 37℃for 5 to 10 minutes until the cells were completely detached. Digestion was terminated by adding serum-containing medium.

5) The cell suspension was pipetted into a round bottom centrifuge tube and centrifuged at 120 Xg for 10 minutes.

6) Cells were resuspended using medium at a final concentration of 1.56X10 ⁶ cells/mL.

MDCKII-MDR1 cell seeding

1) The cell suspension was added to the 96-well Transwell plate upper chamber at 50 μl per well and the final seeding density was 1.45×10 ⁵cells/cm².

2) The medium was changed at intervals of one day after the culture for 4 to 8 days after the inoculation for 24 hours.

Evaluation of cell monolayer membrane integrity

1) MDCKII-MDR1 and MDCKII should be fully pooled and differentiated after 4-8 days of culture. At this time, it can be applied to a penetration test.

2) The single layer film resistance was measured with a resistance meter (Millipore, USA) and the resistance per well was recorded.

3) After the measurement, the Transwell plates were returned to the incubator.

4) Calculating the resistance value:

Determination of resistance value (ohms) x film area (cm ²) =teer value (ohm cm ²)

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

Drug penetration test

1) MDCKII-MDR1Transwell plates were removed from the incubator. The cell monolayer membranes were rinsed twice with HBSS (10mM HEPES,pH 7.4) buffer and incubated for 30 min at 37 ℃.

2) The transport rate of the compound from the apical to basal end was determined. 125. Mu.L of HBSS (10mM HEPES,pH 7.4) buffer of test or control drug was added to each well of the upper chamber (top end), and 235. Mu.L of HBSS (10) was added to each well of the lower chamber (bottom end)

MM HEPES, pH 7.4).

3) The rate of transport of the compound from the substrate end to the top end was determined. 285. Mu.L of HBSS (10 mM HEPES, pH 7.4) buffer was added to each well of the upper layer cell (top end), and 75. Mu.L of HBSS (10 mM HEPES, pH 7.4) buffer of the test drug or control drug was added to each well of the lower layer cell (bottom end).

4) After combining the upper and lower transfer devices, incubation was performed for 2 hours at 37 ℃.

5) After incubation was completed, 50 μl samples were taken from each well of the Transwell plate upper and lower chambers, respectively, and added to new sample tubes. 4 volumes of acetonitrile containing internal standard (200 nM alprazolam, 200nM labetalol, 200nM diclofenac, 100) were added to the sample tube

NM tolbutamide), vortexed for 5 minutes, and centrifuged at 3,220g for 15 minutes. 100. Mu.L of supernatant was aspirated and diluted with equal volumes of water before LC-MS/MS analysis. All samples were prepared in triplicate.

6) The integrity of the cell monolayer after 2 hours incubation was assessed by leakage of the fluorescein, and the fluorescein stock was diluted to a final concentration of 100 μm using HBSS (10mM HEPES,pH 7.4). A fluorescent yellow solution (100. Mu.L) was added to each well of the upper Transwell plate, and a 300. Mu.L HBSS (10mM HEPES,pH 7.4) was added to each well of the lower receiving plate. After incubation at 37 ℃ for 30 minutes, 80 μl of solution was aspirated from each well upper and lower layer into a new 96-well plate. Excitation wavelength 485nm and emission wavelength using an enzyme-labeled instrument

Fluorescence measurement was performed at 530 nm.

2. Data processing

Data were calculated using Excel, and apparent permeability coefficients (P _app, units: cm/s) of the compounds were calculated using the following formula:

The membrane area in the formula is Transwell-96 well plate membrane area (0.143 cm ²), and the incubation time unit is seconds(s).

The efflux rate is calculated using the following formula:

TABLE 12 efflux of test compounds

End product numbering	ER (discharge rate Efflux Ratio)
		5	1.6

EXAMPLE 4 in vivo case pharmacokinetic testing of Compounds in mice

The aim of the experiment is to take an ICR mouse as a test object, measure a compound administered by lavage (PO) by using an LC/MS/MS method, detect the drug concentration of the compound in plasma at the moments of 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h, study the pharmacokinetic behavior of the compound in the mouse and evaluate the pharmacokinetic characteristics of the compound.

Pharmaceutical formulation the compounds were formulated as clear solutions using 10% dmso+10% Solutol hs15+5% Cremophor el+20% PEG400+55% (20% captisol in water) as vehicle for PO dosing, the dosing method was cassette dosing (cassette dosing), the dosing dose of the compounds was 10mg/kg, and the pharmacokinetic parameters results are shown in table 13.

TABLE 13 in vivo case pharmacokinetic test results in mice

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

The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.

Claims

1. A nitrogen-containing heteroaromatic ring compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof:

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} _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 alkylthio, 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 attached C atom 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).

2. The nitrogen-containing heteroaromatic ring compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein, in Formula I, M is N or CR ³ ;

^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} _alkylthiol , 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.

3. 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's;

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;

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

More preferably, A is selected from the following groups:

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

4. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 3, wherein, in Formula I: Y ¹ 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.

5. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 4, wherein, in Formula I: Y ² is a chemical bond, a 3-12 membered heterocyclic group or NR ⁷ , 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;

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;

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).

6. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 5, wherein, in Formula I: E is phenyl or a 5-6-membered heteroaryl group, and the phenyl group and the 5-6-membered heteroaryl group 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 ;

Preferably, 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;

^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 ;

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:

7. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 6, wherein, in Formula I: R ¹ is a halomethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, 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 and ^Rb, taken together with 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:

8. The nitrogen-containing heteroaromatic ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 7, wherein, in Formula I: R ² 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 ;

X is N or CR ⁴ ;

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;

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;

Z is C(═O) or S(O) ₂ ;

L ₁ is NR ⁸ or O;

_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 ;

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;

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 ;

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 ′;

or ^Ra and ^Rb, taken together with 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 or 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 ;

X is N or CR ⁴ ;

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

Y ¹ 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;

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, wherein 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 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;

Z is C(═O) or S(O) ₂ ;

L ₁ is NR ⁸ ;

_L2 is a chemical bond, O, CH or C(=O);

E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, and the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene and pyrazole are optionally substituted with one or more ^Re ;

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;

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 ;

A is selected from the following groups:

Z is C(＝O);

L ₁ is NR ⁸ ;

_L2 is a chemical bond, O, CH or C(=O);

G is selected from the following groups:

^R1 is selected from the following groups:

Most preferably, the compound represented by formula I is selected from the following compounds:

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient;

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

10. Use of the compound according to any one of claims 1 to 9 or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and/or the pharmaceutical composition according to claim 9 in treating diseases mediated by abnormal HER2;

Preferably, the disease is a tumor disease;

More preferably, the tumor 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.