Fused ring compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a fused ring compound, and a preparation method therefor and a use thereof. The structure of the fused ring compound is as shown in formula I: formula I, wherein the definitions of (II) or (III), X1, X2, X3, X4, X5, X6, Y, L, L1, L2, A, Z, E, G, R1, R2, and R3 are as described in the description. The fused ring compound has a potent and highly selective inhibitory effect on epidermal growth factor receptor 2 (HER2), and can be used for the treatment of related diseases induced by HER2 abnormalities, especially the treatment of cancer diseases.

Description

Fused ring compounds, preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to fused ring compounds, a preparation method and application thereof. BACKGROUND

[0002] The human epidermal growth factor receptor 2 (HER2, ErbB2) gene is located on the long arm of chromosome 17 (17q21), and is one of the four members of the ErbB family (EGFR / HER1 / ErbB1, HER2 / ErbB2, HER3 / ErbB31 and HER4 / ErbB4), and has tyrosine kinase activity. At present, no ligand that can directly act on HER2 has been found. HER2 can activate the downstream MEK / ERK / MAPK pathway and the PI3K / AKT bypass by forming a heterodimer with other members of the ErbB family, and finally promote cell growth, proliferation and division, etc.

[0003] Overexpression (upregulation) or overactivity (amplification or mutation) of HER2 has been confirmed to be associated with many cancers, including breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, endometrial cancer and glioblastoma. The detection rates of HER2 overexpression in lung cancer, breast cancer, gastric cancer, cholangiocarcinoma, ovarian cancer and endometrial cancer are about 2.5%, 15%-25%, 20%, 20%, 27%, 18%-80%, respectively.

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

[0005] Currently approved drugs for the treatment of HER2 abnormalities in the clinic include monoclonal antibodies (mAbs) (trastuzumab, pertuzumab, etc.), small molecule tyrosine kinase inhibitors (TKIs) (lapatinib, tucatinib, neratinib, pyrotinib, etc.), and antibody conjugate drugs (ADCs) (emtansine, deruxtecan).

[0006] Monoclonal antibodies and antibody conjugate drugs have poor selectivity for wild-type EGFR, and patients are prone to adverse reactions such as skin rash and diarrhea. Antibody conjugate drugs, due to the presence of a chemotherapy drug structure fragment in the structure, have a higher proportion of hematological abnormalities associated with chemotherapy drugs, such as deruxtecan, at a dose of 5.4 mg / kg, in HER2 mutant non-small cell lung cancer patients, the incidence of grade 3 and above neutropenia, lymphopenia, and hemoglobin reduction was 12%, 16%, and 10%, respectively. Moreover, deruxtecan has 12% of patients with interstitial pneumonia in metastatic breast cancer and HER2 mutant non-small cell lung cancer patients. Currently approved TKIs include selective TKIs (tucatinib) and non-selective TKIs (lapatinib, neratinib, and pyrotinib), which show moderate antitumor activity against wild-type HER2, but have poor effects on the most common HER2 exon 20 insertion mutation. In addition, non-selective TKIs have poor selectivity for wild-type EGFR, and are prone to adverse reactions such as skin rash and diarrhea. Therefore, it is of great significance to develop a HER2 inhibitor with selectivity, the ability to penetrate the blood-brain barrier, and potential inhibition of HER2 exon 20 insertion mutations. SUMMARY

[0007] To solve the defects of the prior art, the present application aims to provide a fused ring compound and a preparation method and application thereof. The fused ring compound of the present application has good inhibitory activity against HER2 exon 20 insertion mutations, and has high selectivity for wild-type EGFR, and can be used as a treatment for diseases related to HER2 abnormalities, especially cancer diseases.

[0008] The present application is achieved by the following technical solutions.

[0009] In a first aspect, the present application provides a compound having the structure shown in formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof:

[0010] In formula I,

[0011] represents a single bond or a double bond;

[0012] X 1 , Xeach independently N or C, and X 1 , X 2 are not simultaneously N;

[0013] X 3 is N, C or CR 4 ;

[0014] X 4 is N, CR 5 , O or S;

[0015] X 5 is N, C or CR 6 ;

[0016] X 6 is a bond, N or CR 7 ; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 at most 3 are simultaneously N, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 two adjacent bonds connected between X 8 cannot be simultaneously double bonds;

[0017] L is absent or O, N(R 9 ), C(R 10 R 8 ), C(=O), S, S(=O) or S(=O)2;

[0018] L1is absent or O, N(R 9 ), C(R 10 R 11 ), -OR 11 -, -NR 12 -, C(=O), S, S(=O) or S(=O)2;

[0019] L2is absent or N(R 13 );

[0020] Y is N or CR 1-6 ;

[0021] A is absent or C 2-6 alkyl, C 2-6 alkenyl, C 14 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, NR14 R 15 , OR 16 , SR 16 , 3-12 membered cycloalkyl-C 1-6 alkylene-, 3-12 membered heterocyclyl-C 1-6 alkylene-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 alkylene-, 3-12 membered heterocyclyl-C 1-6 alkylene- is optionally substituted with one or more R';

[0022] Z is C=0 or S(=0)2;

[0023] E is 6-10 membered aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said 6-10 membered aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S is optionally substituted with one or more R';

[0024] G is 6-12 membered aryl, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S N-oxide containing at least 1 N atom, 6-12 membered aryl-C 1-6 alkylene-, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S N-oxide containing at least 1 N atom-C 1-6 alkylene-, said 6-12 membered aryl, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S N-oxide containing at least 1 N atom, 6-12 membered aryl-C 1-6 alkylene-, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S N-oxide containing at least 1 N atom-C 1-6alkylene- optionally substituted by one or more R';

[0025] R 1 haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 4-6 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 4-6 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC x alkyl, haloC y alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-3 alkyl, haloC 1-3 alkyl, haloC

[0026] R 2 , R 3 each independently a hydrogen atom, a deuterium atom, a halogen, a cyano group, an OR a , NR b R c , C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC

[0027] R4 5 6 7 8 9 10 12 13 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3-12 membered cycloalkyl group, a C 1-6 alkoxy group, an amino group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a 3-12 membered heterocyclyl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, S(=O), S(O)2, an oxo (=O), the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the 3-12 membered cycloalkyl group, the C 1-6 alkoxy group, the amino group, the C 1-6 alkylamino group, the di(C 1-6 alkyl)amino group, the 3-12 membered heterocyclyl group is optionally substituted with one or more R’;

[0028] R 11 is a C 1-6 alkylene group, the C 1-6 alkylene group is optionally substituted with one or more R’;

[0029] or, R 3 and R 7 together with the atoms to which they are respectively attached form a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, S(=O), S(=O)2, a 5-12 membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, O, S, a 6-12 membered aryl 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 is optionally substituted with one or more R’;

[0030] or, when X 6 is a bond, R 3 and the attached C atom form L 1 ​​​​​​​​together with the carbon atom to which they are attached form a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, said 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl being optionally substituted by one or more R';

[0031] or R 9 together with the carbon atom to which they are attached form a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, said 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl being optionally substituted by one or more R'; 10 together with the carbon atom to which they are attached form a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, said 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl being optionally substituted by one or more R';

[0032] R 14 , R 15 , R 16 each independently are a hydrogen atom, a C 1-6 alkyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, a 3- to 12-membered cycloalkyl-C 1-6 alkylene group, a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, said C 1-6 alkyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, a 3- to 12-membered cycloalkyl-C 1-6 alkylene group, a 3- to 12-membered heterocyclyl-C 1-6 alkylene group, said C

[0033] or R 14 together with the carbon atom to which they are attached form a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, said 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl being optionally substituted by one or more R'; 15 together with the carbon atom to which they are attached form a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, said 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl being optionally substituted by one or more R';

[0034] R' is selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group with one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, a halo-C 1-6 alkyl group, a halo-C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a hydroxy-C 1-6 alkyl group, an amino-C 1-6 alkyl group, a cyano-C 1-6 alkyl group, OR e , SR e , S(=0)R e , S(=0)2R e , C(=0)R e , C(=0)NR e , C(=0)OR e , NR e R f , NR e C(=0)R f , OC(=0)R e , S(=0)NR f , S(=0)2NR e , NHS(=0)2R e , NHS(=0)R e , NR e C(=0)OR f , NR e C(=0)NR f , -(0)(=0R e )2, P(=0)(R e )2, or oxo (=0), said C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group with one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, a halo-C 1-6 alkyl group, a halo-C 1-6 alkoxy group, a hydroxy-C 1-6 alkyl group, an amino-C 1-6 alkyl group, a cyano-C 1-6 alkyl group is optionally substituted with one or more R";

[0035] each R" is independently a deuterium atom, a halogen, a cyano group, a hydroxy group, an amino group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C2-6 alkynyl, haloC 1-4 alkyl, deuteratedC 1-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, haloC 1-6 alkoxy or oxo (=0);

[0036] R a , R b , R c each independently a hydrogen atom, a deuterium atom, C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkylene-, C 1-6 alkylamino-C 1-4 alkylene-, di(C 1-6 alkyl)amino-C 1-4 alkylene-, 3- to 7-membered cycloalkyl-C 1-4 alkylene-, 3- to 12-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2-C 1-4 alkylene-, 3- to 12-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, haloC 1-6 alkyl, 3- to 7-membered cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkylene-, C 1-6 alkylamino-C 1-4 alkylene-, di(C 1-6 alkyl)amino-C 1-4 alkylene-, 3- to 7-membered cycloalkyl-C 1-4 alkylene-, 3- to 12-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2-C 1-4 alkylene-, 3- to 12-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, S, S(=0), S(=0)2, haloC 1-6 alkyl, 3- to 7-membered cycloalkyl optionally substituted by one or more R';

[0037] R e , R f each independently a hydrogen atom, a deuterium atom, C 1-4 alkyl, haloC 1-4alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2;

[0038] or, R e and R f form, together with the N atom to which they are attached, a 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2;

[0039] R x , R y each independently is a hydrogen atom, a C 1-4 alkyl, halo-C 1-4 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, 3- to 12-membered cycloalkyl-C 1-4 alkylene-, 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2-C 1-4 alkylene-, C 1-4 alkoxy-C 1-4 alkylene- or deuterated C 1-4 alkyl, said C 1-4 alkyl, halo-C 1-4 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, 3- to 12-membered cycloalkyl-C 1-4 alkylene-, 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2-C 1-4 alkylene-, C 1-4 alkoxy-C 1-4 alkylene- or deuterated C 1-4 alkyl is optionally substituted with one or more R';

[0040] or, R x and R y form, together with the N atom to which they are attached, a 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3- to 12-membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2is optionally substituted with one or more R'.

[0041] In certain embodiments, in Formula I, the compound further has a structure represented by Formula II, III, or IV:

[0042] wherein R 20 , R 30 , R40 , R 50 each independently R';

[0043] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y, L, L1, L2, A, Z, G, R 1 , R 2 , R 3 , R' are as defined above.

[0044] In certain embodiments, in formula I, II, III, or IV, X 1 , X 2 each independently C;

[0045] In certain embodiments, in formula I, II, III, or IV, X 3 is N, C, or CR 4 ;

[0046] Preferably, X 3 is N or C.

[0047] In certain embodiments, in formula I, II, III, or IV, X 4 is N or CR 5 .

[0048] In certain embodiments, in formula I, II, III, or IV, X 5 is N, C, or CR 6 ;

[0049] Preferably, X 5 is N or C.

[0050] More preferably, X 5 is C.

[0051] In certain embodiments, in formula I, II, III, or IV, X 6 is a bond, N, or CR 7 ;

[0052] Preferably, X 6 is a bond or CR 7 ;

[0053] In certain embodiments, X 3 , X 4 , X 5 , X 6 is at most 3 are simultaneously N, and X 1 , X2 , X 3 , X 4 , X 5 , X 6 The two adjacent linked chemical bonds between X and X cannot be double bonds at the same time.

[0054] In certain embodiments, in Formula I, II, III, or IV, L is absent or O, N(R 8 ), or C(R 9 R 10 );

[0055] Preferably, L is absent or O or C(R 9 R 10 );

[0056] More preferably, L is O or C(R 9 R 10 ).

[0057] In certain embodiments, in Formula I, II, III, or IV, L1is absent or O, N(R 8 ), C(R 9 R 10 ), -OR 11 -, or -NR 11 -;

[0058] Preferably, L1is absent or O, N(R 8 ), -OR 11 -, or -NR 11 -;

[0059] More preferably, L1is absent or O, N(R 8 ).

[0060] In certain embodiments, in Formula I, II, III, or IV, L2is absent or N(R 12 ).

[0061] In certain embodiments, in Formula I, II, III, or IV, Y is N or CR 13 .

[0062] Preferably, in Formula I, II, III, or IV, Y is N.

[0063] In certain embodiments, in Formula I, II, III, or IV, A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, C1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene- is optionally substituted by one or more R';

[0064] Preferably, A is absent or is methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, acridineyl, piperazine, morpholinyl, azacycloheptanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopentane Diene[C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinemethyl, tetrahydropyrrolemethyl, acridinemethyl, morpholinemethyl, piperidineethyl, tetrahydropyrroleethyl, acridineethyl, morpholineethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2. 2.1] Heptane, wherein the methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, acridinel, piperazinyl, morpholinyl, azacycloheptyl, tetrahydropyridyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopentadiene And [C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinemethyl, tetrahydropyrrolemethyl, acridinemethyl, morpholinemethyl, piperidineethyl, tetrahydropyrroleethyl, acridineethyl, morpholineethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1] heptane is optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino or oxo (=0).

[0065] More preferably, A is absent or selected from the following groups:

[0066] the above groups are optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino or oxo (=0).

[0067] In certain embodiments, in formula I, II, III or IV, Z is C=0 or S(=0)2;

[0068] Preferably, Z is C=0.

[0069] In certain embodiments, in formula I, E is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S is optionally substituted by 1, 2, 3 or 4 R';

[0070] Preferably, in formula I, E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, said phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole is optionally substituted by 1, 2, 3 or 4 R'.

[0071] In certain embodiments, in formula I, II, III or IV, G is phenyl, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2alkylene-, 6-12 membered heteroaryl-C 1-2 alkylene-, 6 membered heteroaryl N-oxide-C 1-2 alkylene- optionally substituted by one or more R';

[0072] G is preferably phenyl, pyridyl, phenylmethyl, pyridylmethyl, said phenyl, pyridyl, phenylmethyl, pyridylmethyl, optionally substituted by 1, 2, 3 or 4 deuterium atoms, F, CI, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

[0073] denotes a single or double bond;

[0074] B ring is pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine;

[0075] X a , X b , X c each independently N or CH;

[0076] X 1a is a bond, N, CH, CH2, S, O, S(O) or S(O)2;

[0077] X 2a is N, CH, CH2, O, S, S(O) or S(O)2;

[0078] X 3a , X 4a each independently N or C, and X 3a and X 4a are not simultaneously N, X 1a , X 2a and X 3a are not simultaneously N;

[0079] X 5a is a bond, N, CH, CH2, O or S;

[0080] X 6a is N, O, S or CH;

[0081] n is 0, 1 or 2;

[0082] Preferably, in formula I, II, III or IV, G is phenyl, pyridyl, phenylmethyl, pyridylmethyl or is selected from the group consisting of:

[0083] said phenyl, pyridyl, phenylmethyl, pyridylmethyl or the above mentioned group is optionally substituted by 1, 2, 3 or 4 halogen, deuterium atom, F, CI, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy;

[0084] More preferably, in formula I, II, III or IV, G is selected from the group consisting of:

[0085] In certain embodiments, in formula I, II, III or IV, R 1 is dihalogenmethyl, C 2-4 alkenyl, C 2-4 alkynyl, epoxypropyl or C 4-6 cycloalkenyl, said dihalogenmethyl, C 2-4 alkenyl, C 2-4 alkynyl, epoxypropyl or C 4-6 cycloalkenyl is optionally substituted by one or more halogen, deuterium atom, C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl, or NR x R y , R 1-4 each independently is hydrogen atom, C 1-3 alkyl, C 1-3 alkoxy-C x alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl is optionally substituted by one or more R';

[0086] R x , R y each independently is hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4Alkoxy-C 1-4 alkylene-, the C 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, 4-7 membered heterocyclic groups containing one or more heteroatoms selected from N, O, S, and C, 3-6 membered cycloalkyl-C 1-4 Alkylene, containing one or more 4-6 membered heterocyclic groups selected from N, O, and S heteroatoms -C 1-4 alkylene- or C 1-4 Alkoxy-C 1-4 Alkylenes are optionally substituted with one or more R′;

[0087] Or, R x With R y Together with the attached N atom, it forms a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S(=O), and S(=O)2, wherein the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, and S is optionally replaced by one or more R′.

[0088] Preferably, R 1 The dihalomethyl, vinyl, propynyl, ethynyl, propynyl, butynyl, propylene oxide, cyclobutenyl, cyclopentenyl, or cyclohexenyl groups are optionally replaced by one or more F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, acrylidine, pyrrolidine, piperidinyl, propylene oxide, propylene oxide, butyloxide, deuterium, phenyl, pyridinyl, or NR atoms. x R y The methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, acridine, pyrrolyl, piperidinyl, propylene oxide, butyl oxide, phenyl, and pyridinyl groups are optionally substituted by one or more R′.

[0089] R x R y Each of the following is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, acridinemethyl or acridineethyl is optionally substituted by one or more R′;

[0090] Or, R x With R ytogether with the attached N atom form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptanyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptanyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl being optionally substituted by one or more R';

[0091] More preferably, in formula I, II, III or IV, R 1 is selected from the following groups:

[0092] In certain embodiments, in formula I, II, III or IV: R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0093] Preferably, in formula I, II, III or IV, R 2 is a hydrogen atom, R 3 is selected from a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0094] In certain embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , R9 R 10 R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group.

[0095] In certain embodiments, R 11 is a methylene group, an ethylene group, a propylene group.

[0096] In certain embodiments, R 13 is a hydrogen atom, a halogen, a cyano group.

[0097] In certain embodiments, R' is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a methoxymethyl group, a methoxyethyl group, a methylaminoethyl group, a dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or an oxo (=0) group, said methyl group, ethyl group, propyl group, isopropyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, hydroxyl group, methoxy group, ethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, methylamino group, ethylamino group, methoxymethyl group, methoxyethyl group, methylaminoethyl group, dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, Cl, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group.

[0098] In certain specific embodiments, in formula I, II, III, or IV:

[0099] represents a single bond or a double bond;

[0100] X 1 , X 2 each independently is C;

[0101] X 3 is N, C or CR 4 ;

[0102] X 4 is N or CR 5 ;

[0103] X 5 is N, C or CR 6 ;

[0104] X 6 is a bond, N or CR 7 ; X 3 , X 4 , X 5 , X 6 at most 3 are simultaneously N, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 two adjacent bonds connected between X

[0105] L is absent or O, N(R 8 ) or C(R 9 R 10 );

[0106] L1is absent or O, N(R 8 ), C(R 9 R 10 ), -OR 11 - or -NR 11 -;

[0107] L2is absent or N(R 12 );

[0108] Y is N or CR 13 ;

[0109] A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4alkylene- optionally substituted by one or more R';

[0110] Z is C=0 or S(=0)2;

[0111] E ring is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, is optionally substituted by 1, 2, 3, or 4 R';

[0112] G is phenyl, 6-12 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene-, said phenyl, 6-12 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene- optionally substituted by one or more R';

[0113] R 1 is dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, oxetanyl or C 4-6 cycloalkenyl, said dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, oxetanyl or C 4-6 cycloalkenyl optionally substituted by one or more halogen, deuterium atom, C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, phenyl, or NR x R y substituted, said C 1-4 alkyl, C 1-3 alkoxy-C 1-3alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl optionally substituted with one or more R';

[0114] R x , R y each independently is a hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene- optionally substituted with one or more R';

[0115] or, R x and R y and the connected N atom form a 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S optionally substituted with one or more R';

[0116] R 2 , R 3 each independently is a hydrogen atom, amino, deuterium atom, halogen, cyano, methyl, ethyl, isopropyl or cyclopropyl;

[0117] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, deuterium atom, halogen, cyano, methyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, aminomethyl, aminoethyl or oxo(=0);

[0118] R 11 is a hydrogen atom, a halogen, a cyano group;

[0119] R 13 is a hydrogen atom, a halogen, a cyano group;

[0120] R' is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a methoxymethyl group, a methoxyethyl group, a methylaminoethyl group, a dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or an oxo (=0) group, the methyl group, the ethyl group, the propyl group, the isopropyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the difluoromethyl group, the trifluoromethyl group, the difluoroethyl group, the trifluoroethyl group, the hydroxyl group, the methoxy group, the ethoxy group, the difluoromethoxy group, the trifluoromethoxy group, the difluoroethoxy group, the trifluoroethoxy group, the methylamino group, the ethylamino group, the methoxymethyl group, the methoxyethyl group, the methylaminoethyl group, the dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, Cl, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group.

[0121] In certain embodiments, in Formula I, II, III, or IV:

[0122] represents a single bond or a double bond;

[0123] X 1 , X 2 each independently is C;

[0124] X 3 is N, C, or CR 4 ;

[0125] X 4 is N, or CR 5 ;

[0126] X 5 is N, C, or CR 6 ;

[0127] X6 is a bond, N or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 two adjacent X

[0128] L is absent or O, N(R 8 ) or C(R 9 R 10 );

[0129] L1is absent or O, N(R 8 ), C(R 9 R 10 ), -OR 11 - or -NR 11 -;

[0130] L2is absent or N(R 12 );

[0131] Y is N or CR 13 ;

[0132] A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, 3-6 membered cycloalkyl-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, 3-6 membered cycloalkyl-C 1-4 alkylene- is optionally substituted with one or more R';

[0133] Z is C=O;

[0134] E ring is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S is optionally substituted with 1, 2, 3 or 4 R';

[0135] G is phenyl, pyridyl, phenylmethyl, pyridylmethyl, said phenyl, pyridyl, phenylmethyl, pyridylmethyl, optionally substituted with 1, 2, 3, or 4 deuterium atoms, F, Cl, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, deuteromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0136] represents a single or double bond;

[0137] B ring is pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, or triazine;

[0138] X a , X b , X c each independently is N or CH;

[0139] X 1a is a bond, N, CH, CH2, S, O, S(O), or S(O)2;

[0140] X 2a is N, CH, CH2, O, S, S(O), or S(O)2;

[0141] X 3a , X 4a each independently is N or C, and X 3a and X 4a are not simultaneously N, X 1a , X 2a and X 3a are not simultaneously N;

[0142] X 5a is a bond, N, CH, CH2, O, or S;

[0143] X 6a is N, O, S, or CH;

[0144] n is 0, 1, or 2;

[0145] R 1halogen, F, Cl, methyl, ethyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, deuterium atom, phenyl, pyridyl, or NR x R y substituted, said methyl, ethyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylene oxide, butylene oxide, phenyl, pyridyl are optionally substituted with one or more R';

[0146] R x , R y each independently is a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl, or azetidinylethyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, adamantyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclobutylethyl, azetidinylmethyl, or azetidinylethyl is optionally substituted with one or more R';

[0147] or, R x and R ytogether with the attached N atom form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a dioxidothiomorpholinyl group, a 7-azabicyclo[2.2.1]heptanyl group, a 9-azabicyclo[3.3.1]nonyl group, a 2-azabicyclo[4.1.0]heptanyl group, a 2-azabicyclo[3.1.0]hexanyl group, a 2-oxa-6-azaspiro[3.4]octanyl group, a 5-oxa-8-azaspiro[3.5]nonanyl group, a 3-azabicyclo[3.1.0]hexanyl group, a 8-oxa-5-azaspiro[3.5]nonanyl group, a tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl group, a 2-oxa-5-azabicyclo[2.2.1]heptanyl group, a 8-oxa-3-azabicyclo[3.2.1]octanyl group, a 3-azabicyclo[3.2.1]octanyl group, optionally substituted by one or more R';

[0148] R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group;

[0149] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group;

[0150] R 11 is a methylene group, an ethylene group, a propylene group;

[0151] R13 is a hydrogen atom, halogen, cyano;

[0152] R' is a hydrogen atom, deuterium atom, F, Cl, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=O)CH3, S(=O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(=O)2NCH3, P(=O)(CH3)2, or P(=O)(CH2CH3)2, or oxo (=O), said methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=O)CH3, S(=O)2CH3, C(=O)CH3, C(=O)NCH3, NHC(=O)CH3, S(=O)2NCH3, P(=O)(CH3)2, or P(=O)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, Cl, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl.

[0153] In other embodiments, in formula II, II, III, or IV:

[0154] represents a single or double bond;

[0155] X 1 , X 2 each independently is C;

[0156] X 3 is N or C;

[0157] X 4 is N or CR 5 ;

[0158] X 5 is N or C;

[0159] X 6 is a bond or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 are simultaneously N, and X 1, X 2 , X 3 , X 4 , X 5 , X 6 two adjacent R 9 groups linked together can not both be double bonds;

[0160] L is absent or O or C(R 10 );

[0161] L1is absent or O, N(R 8 ), -OR 11 - or -NR 11 -;

[0162] L2is absent or N(R 12 );

[0163] Y is N or CR 13 ;

[0164] A is absent or is methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, acridineyl, piperazinyl, morpholinyl, azacycloheptanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopentadiene and [C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinemethyl, tetrahydropyrrolemethyl, acridinemethyl, morpholinemethyl, piperidineethyl, tetrahydropyrroleethyl, acridineethyl, morpholineethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2. 1] Heptane, wherein the methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, acridineyl, piperazine, morpholinyl, azacycloheptyl, tetrahydropyridyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-1,7-diazaspiro[4.5]dec-1-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopentadiene and [C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinemethyl, tetrahydropyrrolemethyl, acridinemethyl, morpholinemethyl, piperidineethyl, tetrahydropyrroleethyl, acridineethyl, morpholineethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1] heptane is optionally substituted with one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino, or oxo (=0);

[0165] Z is C=0;

[0166] E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene, or pyrazole, optionally substituted with 1, 2, 3, or 4 R';

[0167] G is phenyl, pyridyl, phenylmethyl, pyridylmethyl, or is selected from the group consisting of:

[0168] the phenyl, pyridyl, phenylmethyl, pyridylmethyl, or the above group is optionally substituted with 1, 2, 3, or 4 deuterium atom, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy;

[0169] R 1 is selected from the group consisting of:

[0170] R 2 , R 3 each independently is a hydrogen atom, amino, deuterium atom, halogen, cyano, methyl, ethyl, isopropyl, or cyclopropyl;

[0171] R 5 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, deuterium atom, halogen, cyano, methyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, aminomethyl, aminoethyl, or oxo (=0);

[0172] R 11 is methylene, ethylene, propylene;

[0173] R 13 is a hydrogen atom, halogen, cyano;

[0174] R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), said methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, CI, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl.

[0175] In yet other embodiments, in formula I, II, III, or IV:

[0176] represents a single or double bond;

[0177] X 1 , X 2 each independently is C;

[0178] X 3 is N or C;

[0179] X 4 is N or CR 5 ;

[0180] X 5 is N or C;

[0181] X 6 is a bond or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 are simultaneously N, and X 1 , X 2 , X3 , X 4 , X 5 , X 6 two adjacent R

[0182] L is O or C(R 9 R 10 );

[0183] L1 is absent or O, N(R 8 ), -OR 11 - or -NR 11 -;

[0184] L2 is absent or N(R 12 );

[0185] Y is N or CR 13 ;

[0186] A is absent or selected from the group consisting of:

[0187] the above group is optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino or oxo (=0);

[0188] Z is C=0;

[0189] E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, said phenyl, pyridyl, pyrimidine, pyridazine, pyrazine being optionally substituted by 1, 2, 3 or 4 R';

[0190] G is selected from the group consisting of:

[0191] R 1 is selected from the group consisting of:

[0192] R 2 , R 3 each independently is a hydrogen atom, amino, deuterium atom, halogen, cyano, methyl, ethyl, isopropyl or cyclopropyl;

[0193] R 5 , R 7 , R 8 , R 9 , R 10 , R12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group;

[0194] R 11 is a methylene group, an ethylene group, a propylene group;

[0195] R 13 is a cyano group;

[0196] R' is a hydrogen atom, a deuterium atom, F, Cl, a cyano group, a nitro group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a methoxymethyl group, a methoxyethyl group, a methylaminoethyl group, a dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or an oxo (=0) group, said methyl group, ethyl group, propyl group, isopropyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, hydroxyl group, methoxy group, ethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, methylamino group, ethylamino group, methoxymethyl group, methoxyethyl group, methylaminoethyl group, dimethylaminoethyl group, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, Cl, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group.

[0197] In a more particular embodiment, the compound of formula I is selected from the group consisting of:

[0198] In a second aspect, the present application provides a method for preparing a compound of formula I, the method comprising the following reaction steps:

[0199] (1) compound I-1 is reacted with compound I-2 to form compound I-3;

[0200] (2) compound I-3 is reacted with compound I-4 to form compound I-5;

[0201] (3) compound I-5 is deprotected to form compound I-6;

[0202] (4) compound I-6 is reacted with compound I-7 to form compound I-8;

[0203] (5) compound I-8 is deprotected to form compound I-9;

[0204] (6) compound I-9 is reacted with compound I-10 to form a compound of formula I;

[0205] In certain embodiments, the present application provides a method for preparing a compound of formula I-I, the method comprising the following reaction steps:

[0206] (1) compound I-6 is reacted with tert-butyl carbazate to form compound I-12;

[0207] (2) compound I-12 is deprotected to form compound I-13;

[0208] (3) compound I-13 is reacted with compound I-14 to form compound I-15;

[0209] (4) compound I-15 is reacted with R 2 -formamide to form compound I-16;

[0210] (5) compound I-16 is deprotected to form compound I-17;

[0211] (6) compound I-17 is reacted with compound I-9 or compound I-10 or compound I-11 to form a compound of formula I-I;

[0212] In certain embodiments, the present application provides another method for preparing a compound of formula I-I, the method comprising the following reaction steps:

[0213] (1) compound I-13 is reacted with compound I-18 to form compound I-19;

[0214] (2) compound I-19 is reacted with R 2 -formamide to form compound I-20;

[0215] (3) compound I-20 is deprotected to form compound I-21;

[0216] (4) reacting compound I-21 with compound I-22 to form compound I-16;

[0217] (5) deprotecting compound I-16 to form compound I-17;

[0218] (6) reacting compound I-17 with compound I-9 or compound I-10 or compound I-11 to form a compound of Formula I-I;

[0219] In certain embodiments, the present application provides a method of preparing a compound of Formula I-II, comprising the following reaction steps:

[0220] (1) reacting compound I-6 with compound M1 to form compound I-23;

[0221] (2) reacting compound I-23 with compound I-24 to form compound I-25;

[0222] (3) reducing compound I-25 to form compound I-26;

[0223] (4) reacting compound I-26 with compound I-9 or compound I-10 or compound I-11 to form a compound of Formula I-II;

[0224] In certain embodiments, the present application provides a method of preparing a compound of Formula V, comprising the following reaction steps:

[0225] (1) reacting compound V-1 with V-2 to form compound V-3;

[0226] (2) reacting compound V-3 with V-4 to form compound V-5;

[0227] (3) ring closing compound V-5 to form compound V-6;

[0228] (4) reacting compound V-6 with compound I-22 to form compound V-7;

[0229] (5) hydrolyzing compound V-7 to form compound V-8;

[0230] (6) decarboxylating compound V-8 to form compound V-9;

[0231] (7) deprotecting compound V-9 to form compound V-10;

[0232] (8) reacting compound V-10 with compound I-9 or compound I-10 or compound I-11 to form a compound of Formula V;

[0233] wherein M is: M1is: X r is a halogen atom; P 1 , P 2 each independently is a protecting group, including but not limited to Boc, Cbz, CHO, (CH3)2NCH; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y, L, L1, L2, A, Z, E, G, R 1 , R 2 , R 3 are defined as previously defined.

[0234] In a third aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient;

[0235] Preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, rub, spray.

[0236] In a fourth aspect, the present application provides use of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, or a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient, in the preparation of a medicament for preventing and / or treating a disease mediated by HER2 abnormality.

[0237] Preferably, the disease is a neoplastic disease.

[0238] More preferably, the neoplastic disease includes head and neck cancer, nasopharyngeal carcinoma, 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, non-small cell lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0239] In a fifth aspect, the present application provides a method of treating a disease mediated by HER2 abnormality, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition thereof.

[0240] Preferably, the disease is a neoplastic disease.

[0241] More preferably, the neoplastic disease comprises head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, non-small cell lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0242] In a sixth aspect, the present application provides a method of treating a neoplasm, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition thereof.

[0243] The patient is preferably a mammal, and the mammal is preferably a human.

[0244] In certain embodiments, the mode of administration comprises oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.

[0245] In certain embodiments, the neoplasm comprises head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, non-small cell lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma.

[0246] The compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition thereof according to the present application can enter the body by any suitable route, such as by oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal or subcutaneous route.

[0247] In certain embodiments, the compounds provided in the present application, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically labeled, deuterated, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof, can be formulated into dosage forms suitable for pharmaceutical release, administration by injection routes (such as subcutaneous, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracerebral, intradermal, intraperitoneal, transtracheal, epicutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes (such as oral, enterally, buccal, nasal, intranasal, mucosally, epicutaneously, transdermally, topically, ophthalmically, pulmonarily, sublingually, rectally, vaginally, or epicutaneously).

[0248] Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions, and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders, and granules, dosage forms for topical application or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches, and inhalants, dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compounds and suitable excipients under suitable conditions, and the preparation methods and processes are well known, such as provided by Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0249] In certain embodiments, HER2 abnormality refers to HER2 gene mutation, HER2 amplification, or HER2 overexpression;

[0250] Preferably, the HER2 gene mutation includes exon 18-21 mutation, transmembrane domain mutation, and extracellular region mutation; the mutation includes point mutation (e.g., exon 20 point mutation), deletion mutation, and insertion mutation (e.g., exon 20 insertion mutation);

[0251] More preferably, the exon 20 insertion mutations include Y772_A775dup, G776delinsVC, G778_P780dup, G776delinsLC, E770delinsEAYVM, E770_A771insAYVM, M774delinsWLV, A775delinsAYVMA, A775_G776insVVMA, A775_G776insSVMA, A775_G776insTVMA, G776delinsAVGC, G776delinsVV, G776delinsVG, G776_V777delGinsCVC, G776_V777delGinsVC, V777delinsAPL, V777_G778insC, G778insGSP, G778_S779insCPG; the exon 20 point mutations include G776C, G776D, G776S, G776V, V777L, D778H, V782I, T791A, L806P, R811L, N813T, R816C, Q820K, Q828H.

[0252] In certain embodiments, the compounds or pharmaceutical compositions of the present application can be administered simultaneously, sequentially or separately with one or more additional pharmacologically active agents to achieve additive or synergistic effects in the body. For example, the compounds of the present application can be combined with additional pharmacologically active agents in a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Additional pharmacologically active agents that can be administered simultaneously with the compounds of the present application for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal antibodies or ADCs, etc., such as: Osimertinib, Ametanib, Foretinib, Bemforitinib, Olmutinib, Lazertinib, PLB1004, Afatinib, Dacomitinib, Erlotinib, Gefitinib, EKB-569, Cetuximab, Panitumumab, Amivantamab, Lapatinib, Neratinib, Tucatinib, Trastuzumab, Pertuzumab, Margetuximab, Enavatuzumab, Deruxtezumab, etc.; 2) inhibitors of downstream pathway or other pathway targets, including but not limited to MEK, RET, PI3K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (such as CDK4 / 6), etc.For example, trametinib, binimetinib, selumetinib, pacritinib, idelalisib, Copanlisib, Duvelisib, Alpelisib, Umbralisib, Parsaclisib, rapamycin, temsirolimus, everolimus, carmotinib, tipifarnib, sevozatinib, golvatinib, berzosertib, cabozantinib, Emibetuzumab, Telisotuzumab, niraparib, palbociclib, ribociclib, abemaciclib, etc.; 3) Anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) Apoptosis inducers (such as Bcl-2), such as: Obatoclax, Venetoclax, etc.; 5) Chemotherapeutic drugs, such as: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, bacillus calmette-guerin, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carmustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole, leucovorin, pentostatin, plicamycin, procarbazine, raltitrexed, porfimer sodium, rituximab, streptozocin, suramin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triethylene thiophosphoramide, chloromethane, topotecan titanocene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0253] In certain embodiments, the compounds provided herein can be used simultaneously with an immunotherapeutic agent. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as Durvalumab; tumor cell multidrug resistance reversal agents (such as verapamil), mycophenolic acid ester, thalidomide, cyclosporine, and monoclonal antibodies.

[0254] In some embodiments, the compounds provided by this invention can be used simultaneously with non-chemical methods for cancer treatment. In some embodiments, the compounds provided by this invention can be used simultaneously with radiotherapy. In some embodiments, the compounds provided by this invention can be used in combination with surgery, tumor hyperthermia, focused ultrasound therapy, cryotherapy, or a combination of these therapies.

[0255] definition

[0256] Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and scope of various terms used to describe the invention.

[0257] Indicates a single bond or a double bond.

[0258] Indicates the connection site.

[0259] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix (C a-b Alkyl groups are defined as any alkyl group containing one to two carbon atoms ("a" to "b"). Therefore, for example, C 1-6 Alkyl groups refer to alkyl groups containing 1 to 6 carbon atoms. The alkyl groups can be branched or straight-chain.

[0260] The atoms described in the compounds of this invention include their isotopes; for example, hydrogen may be deuterium or tritium.

[0261] A "bridged ring" refers to a polycyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The ring atoms can be all carbon atoms or one or more of the ring atoms can be selected from N, O, S, S(=O) or S(=O)2. Preferably, it has 7-10 rings.

[0262] A "spirocyclic ring" refers to a polycyclic group in which any two rings share a single carbon atom. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The ring atoms can be all carbon atoms or one or more of the ring atoms can be selected from N, O, S, S(=O), or S(=O)2. Preferably, it has 5-10 rings.

[0263] Fused rings: These are polycyclic groups in which each ring shares two adjacent atoms with other rings in the system. They may contain one or more double bonds or have a fully conjugated π-electron system. The ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, S(=O), or S(=O)2. Preferably, they have 5-10 rings.

[0264] Linked rings: refers to any two or more rings connected by chemical bonds.

[0265] According to the number of rings comprising the group, the group is a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group.

[0266] A cyclic group can be bonded to another group in a variety of ways. If the manner of bonding is not specified, then all possible ways are intended. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

[0267] "Alkyl" means a straight-chain or branched-chain, saturated hydrocarbon group including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and other similar groups. Preferred is C 1-8 alkyl. More preferred is C 1-6 alkyl. More preferred is C 1-4 alkyl. The alkyl group includes monovalent or polyvalent, such as alkylene. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be at any point of attachment, and the substituents are preferably the following groups:

[0268] deuterium atom, halogen, cyano, nitro, azido, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-6 heteroalkenyl, 3- to 12-membered saturated or unsaturated cycloalkyl, 3- to 12-membered saturated or unsaturated heterocyclyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, deuterated C 1-10 alkyl, deuterated C 1-10 alkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, oxo (=0).

[0269] "Cycloalkyl" means a saturated monocyclic or polycyclic cyclic hydrocarbon group, which can be combined with other groups. The cycloalkyl group includes monovalent or polyvalent. The cycloalkyl group includes cycloalkenyl. Monocyclic cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Preferred is 3- to 8-membered cycloalkyl. More preferred is 3- to 6-membered cycloalkyl. Polycyclic cyclic hydrocarbon groups include fused, spiro, bridged or bridged cyclic aliphatic groups, including, but not limited to, the following groups:

[0270] "Cycloalkenyl" refers to a partially unsaturated, mono- or polycyclic ring hydrocarbon group having at least one carbon-carbon double bond, but not forming a completely conjugated pi-electron system, which can be combined with other groups. The cycloalkenyl group includes mono- or polyvalent. Monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, and the like. Preferred are 3-8 membered cycloalkenyl groups. More preferred are 3-6 membered cycloalkenyl groups. More preferred are 5-6 membered cycloalkenyl groups. Polycyclic cycloalkenyl groups include fused, spiro, bridged or bridged ring cycloalkenyl groups. Included, but not limited to, are the following groups:

[0271] The cycloalkyl or cycloalkenyl groups can be fused with aryl, heteroaryl or heterocyclyl groups, including, but not limited to, tetrahydronaphthyl, benzocycloheptyl, and the like.

[0272] "Alkenyl" refers to a straight chain, branched chain or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, which alkenyl group includes mono- or polyvalent, including, but not limited to, ethenyl, propenyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl. Preferred are C 2-6 alkenyl groups. More preferred are C 2-4 alkenyl groups.

[0273] "Alkynyl" refers to a straight chain, branched chain or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, which alkynyl group includes mono- or polyvalent, including, but not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. Preferred are C 2-6 alkynyl groups. More preferred are C 2-4 alkynyl groups.

[0274] "Alkylene" refers to a straight chain or branched chain, divalent saturated hydrocarbon group, i.e., one hydrogen atom of an alkyl group is further replaced by a substituent, including, but not limited to, such as "methylene" refers to -CH2-, "ethylene" refers to -CH2CH2-, "propylene" refers to -CH2CH2CH2-, "butylene" refers to -CH2CH2CH2CH2- or -CH2CH(CH3)CH2-.

[0275] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0276] "Haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogens have been replaced by the same or different halogen. Included, but not limited to, such as -CH2Cl, -CHF2, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

[0277] "Aryloxy" means an aryl group, as previously defined, appended to the parent molecular moiety through an oxygen atom. Included within this definition are groups such as phenyloxy, 1-naphthyloxy, 2-naphthyloxy, 2-biphenylyloxy, and 3-biphenylyloxy. Preferably, aryl oxy is phenyloxy.

[0278] "Dialkylamino" means a group having the structure N(C 1-6 "Dialkylamino" means a group having the structure N(C

[0279] "Aryloxy" means an aryl group, as previously defined, appended to the parent molecular moiety through an oxygen atom. Included within this definition are groups such as phenyloxy, 1-naphthyloxy, 2-naphthyloxy, 2-biphenylyloxy, and 3-biphenylyloxy. Preferably, aryl oxy is phenyloxy.

[0280] "Heterocyclyl" refers to a 3-12 membered non-aromatic monocyclic or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings with only single bonds and unsaturated rings with at least one double bond (C=C, C=N or N=N) but not forming a completely conjugated pi-electron system. The heteroatoms are independently selected from N, O, S, nitric oxide (NO), sulfoxide, S(O)(=NH), and sulfone groups. The heterocyclyl groups include monovalent or multivalent. The polycyclic ring systems include fused, bridged, or spirocyclic 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, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and the like. Preferred are 4-7 membered heterocyclyl groups. More preferred are 4-6 membered heterocyclyl groups. Examples of polycyclic heterocyclyl moieties include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, and the like. Examples of unsaturated heterocyclyl moieties include, but are not limited to:

[0281] The heterocyclyl groups can be fused to aryl, heteroaryl, or cycloalkyl groups, including, but not limited to the following groups:

[0282] The heterocyclyl groups are optionally substituted or unsubstituted, and the substituents, if present, are preferably one or more of the following groups: deuterium atom, halogen, CN, nitro, hydroxyl, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C2-6 alkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, haloC 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkoxy, deuteratedC 1-10 alkyl, deuteratedC 1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo(=0).

[0283] "Heteroaryl" means a substituted or unsubstituted 5- or 6-membered monocyclic heteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or bicyclic heteroaromatic ring system, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(=0), S(=0)2, or S, with the remaining ring atoms being carbon atoms. The heteroaryl group includes monovalent or multivalent. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0284] The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl group, including, but not limited to, the following groups:

[0285] The heteroaryl group is optionally substituted or unsubstituted, with the substituted substituent preferably being one or more of the following: deuterium atom, halogen, CN, nitro, hydroxyl, azido, C 1-10 alkyl, C 1-10 alkoxy, haloC 2-10 alkenyl, C 2-10 alkynyl, C 2-6 alkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, haloC 1-10 alkyl, haloC 1-10 alkoxy, deuteratedC 1-10 alkyl, deuteratedC 1-10 alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo(=0).

[0286] "Alkoxy" means a straight-chain or branched-chain saturated alkyl group bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, propyloxy, butyloxy, isobutyloxy, t-butyloxy, and other similar groups. Preferably, C 1-8 alkoxy. More preferably, C 1-6 alkoxy. More preferably, C 1-4 alkoxy.

[0287] "Cycloalkoxy" means -O-cycloalkyl, wherein cycloalkyl is as described above. Preferably, C 3-8Cycloalkoxy. Included, but not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and other similar groups.

[0288] "Heterocyclyloxy" means -O-heterocyclyl, wherein heterocyclyl is as described above. Included, but not limited to, azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxepanyloxy, piperidinyloxy and other similar groups.

[0289] "Pharmaceutically acceptable salt" means either a conventional acid addition salt or a base addition salt that retains the biological effectiveness and properties of the compounds of Formula I and is 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, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and organic acids such as acetic, propionic, glycolic, oxalic, stearic, ascorbic, p-toluene sulfonic, salicylic, methane sulfonic, ethanesulfonic, oxalic, succinic, citric, maleic, hydroxymaleic, lactic, fumaric, tartaric, malic, isethionic, benzenesulfonic, trifluoroacetic, mandelic, and the like. Examples of base addition salts include those derived from inorganic bases such as ammonium, calcium, ferric, aluminum, sodium, potassium, zinc, magnesium. Organic bases include salts of primary, secondary and tertiary amines, such as methylamine, di-methylamine, tri-methylamine, di-ethylamine, ethylamine, ethanolamine, and the like. The chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds.

[0290] "Prodrug molecule" means a prodrug that can be converted in vivo to the structure of the compounds of the present application and pharmaceutically acceptable salts thereof.

[0291] "N-oxide" means that when an amine functionality or a heteroaryl group containing N atom is present in a compound, one or more than one N atom can be oxidized to form an N-oxide bond. + The compound is preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl group containing N.

[0292] "Hydrate" means an association including amounts of water.

[0293] "Solvate" means an association including one or more solvent molecules and a compound of the present application. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.

[0294] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present application or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with other chemical components, such as pharmaceutically acceptable carriers, excipients or diluents. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an animal. A pharmaceutical composition can include, as is known in the art, pharmaceutically acceptable excipients to mimic physiological conditions such as pH adjustment and buffering, toxicity adjustment agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

[0295] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or

[0296] Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; (4) powdered tragacanth; (5) malt; (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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) sterile water; (17) saline; (18) Ringer's solution; (19) thickeners, such as acacia; (20) lubricants, such as magnesium stearate; (21) coloring agents; and (22) lubricating agents, such as talc, magnesium stearate and mineral oil. Other suitable excipients include those described in Remington's Pharmaceutical Sciences by E. W. Martin.

[0297] Each pharmaceutically acceptable carrier should be compatible for use with the other ingredients of the formulation, such as the compounds provided herein, and not induce an excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication in a biological setting, and have reasonable benefit / risk ratio.

[0298] The pharmaceutical ingredients can 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.). The methods of preparing pharmaceutical compositions are well known to those skilled in the art and can be prepared according to conventional methods, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). BRIEF DESCRIPTION OF DRAWINGS

[0299] Figure 1 is a graph showing tumor growth curves of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 10;

[0300] Figure 2 is a graph showing the body weight of mice in different groups of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 10;

[0301] Figure 3 is a graph showing tumor growth curves of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 34;

[0302] Figure 4 is a graph showing the body weight of mice in different groups of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 34;

[0303] Figure 5 is a graph showing tumor growth curves of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 45;

[0304] Figure 6 is a graph showing the body weight of mice in different groups of Ba / F3-HER2 A775-G776insYVMA cell subcutaneous xenograft model tumor-bearing mice after administration of final product 45. DETAILED DESCRIPTION

[0305] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0306] It is specifically intended that any substitutions and modifications well known or obvious to those with ordinary skill in the art be within the scope of the application as contemplated by the inventors. It is intended that the application encompass all such substitutions and modifications.

[0307] Unless otherwise indicated, conventional methods or those modifications known or obvious to those with ordinary skill in the art were used. Unless otherwise indicated, all reagents used were commercially available from common chemical suppliers. Molecules, materials, reagents, and the like, were used according to the manufacturer's instructions unless otherwise indicated.

[0308] Preparation of Intermediate 1-15

[0309] Preparation of Intermediate 1.2-tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1 (2H)-carboxylate

[0310] Under nitrogen protection, tert-butyl 2-methyl-5-oxopiperidine-1-carboxylate (2.0 g, 9.38 mmol) was dissolved in THF (40 mL), and cooled to -78 °C. LiHMDS THF solution (1 M, 11.3 mL, 11.26 mmol) was added dropwise, and stirred at -78 °C for 1 h. N-phenyl bis(trifluoromethanesulfonimide) THF solution (20 mL, 3.7 g, 10.32 mmol) was added, and stirred at -78 °C for 1 h. After the reaction was completed, the reaction was restored to room temperature, and ice water (50 mL) was added to the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-30%) as eluent gradient to obtain tert-butyl 2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)-carboxylate (colorless transparent oil, 2 g, 61.8%). MS (ESI m / z = 290.1 [M+H-56] + m / z = 290.1 [M+H-56] + .

[0311] Preparation of Intermediate 2. tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

[0312] Step 1: tert-Butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1 (2H)-carboxylate (pale yellow oil, 8 g, 98.8%) was obtained from tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylate (5.0 g, 23.44 mmol) following the procedure for Step 1. MS (ESI) m / z = 290.0 [M+H-56] + m / z = 290.0 [M+H-56] + .

[0313] Step 2: tert-Butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1 (2H)-carboxylate (brown oil, 7.4 g, 98.8%) was obtained from tert-Butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)-carboxylate (8.0 g, 23.17 mmol) following the procedure for Step 2. MS (ESI) m / z = 268.1 [M+H-56] + m / z = 268.1 [M+H-56] + .

[0314] Preparation of Intermediate 3. tert-Butyl (3-chlorocyclobutyl)(methyl)carbamate

[0315] First step: tert-Butyl (3-hydroxycyclobutyl)carbamate (5.0 g, 26.70 mmol) was dissolved in THF (50 mL), and then imidazole (3.6 g, 53.41 mmol) and TBDPSCl (11.0 g, 40.06 mmol) were added successively. The mixture was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (5%) as the eluent to obtain tert-butyl (3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)carbamate (colorless oil, 8 g, 70.4%). MS (ESI + m / z = 370.1 [M+H-56] + .

[0316] Second step: tert-Butyl (3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)carbamate (8.0 g, 18.80 mmol) was dissolved in DMF (80 mL), and then NaH (60%, 2.3 g, 56.39 mmol) was added successively at 0°C. The mixture was stirred at 0°C for 0.5 h. Then iodomethane (5.3 g, 37.59 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, ice water (250 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (5%) as the eluent to obtain tert-butyl (3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)(methyl)carbamate (colorless oil, 6 g, 72.6%). MS (ESI + m / z = 440.1 [M+H] + .

[0317] Third step: tert-Butyl (3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)(methyl)carbamate (6.0 g, 13.65 mmol) was dissolved in THF (60 mL), and then TBAF solution in THF (1 M, 40.9 mL, 40.94 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (33%) as the eluent to obtain tert-butyl (3-hydroxycyclobutyl)(methyl)carbamate (colorless oil, 2.5 g, 91.0%). MS (ESI + m / z = 202.1 [M+H] + .

[0318] Fourth step: tert-butyl (3-hydroxycyclobutyl)(methyl)carbamate (2.5 g, 12.42 mmol) was dissolved in THF (25 mL) under nitrogen protection, PPh3(6.5 g, 24.84 mmol) and CC14(3.8 g, 24.84 mmol) were added successively, and the mixture was stirred at 50 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (10%) as the eluent to give tert-butyl (3-chlorocyclobutyl)(methyl)carbamate (white solid, 1.5 g, 55.0%). MS (ESI + )m / z = 164.1 [M+H-56] + .

[0319] Preparation of intermediate 4. zinc (1-(tert-butoxycarbonyl)azetidin-3-yl) iodide

[0320] Zinc powder (1.8 g, 28.26 mmol) was dissolved in N,N-dimethylacetamide (20 mL) under nitrogen protection, and trimethylchlorosilane (3.1 g, 28.26 mmol) was added. The mixture was stirred at 40 °C for 2 h. Then tert-butyl 3-iodoazetidine-1-carboxylate (4.0 g, 14.13 mmol) was added, and the mixture was stirred at 40 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give zinc (1-(tert-butoxycarbonyl)azetidin-3-yl) iodide (yellow solid, 5 g, crude).

[0321] Preparation of intermediate 5. 6-amino-3-bromo-2-chlorobenzonitrile

[0322] 2-Amino-6-chlorobenzonitrile (2.0 g, 13.11 mmol) was dissolved in acetonitrile (20 mL), and NBS (2.3 g, 13.11 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, ice water (10 mL) was added to the reaction mixture, and a solid was precipitated. The solid was filtered, and the filter cake was dried to give 6-amino-3-bromo-2-chlorobenzonitrile (pink solid, 2.9 g, crude). MS (ESI + )m / z = 231.0 [M+H] + .

[0323] Preparation of intermediate 6. 6-amino-3-bromo-2-methylbenzonitrile

[0324] Dissolve 2-amino-6-chlorobenzonitrile (2.0 g, 15.13 mmol) in DMF (20 mL), add NBS (2.7 g, 15.13 mmol), and stir at 70 °C for 2 h. After the reaction is completed, cool to room temperature, add water (15 mL) to the reaction solution, extract the mixture with ethyl acetate (40 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate the resulting residue by silica gel column chromatography using ethyl acetate / petroleum ether (0-40%) as the eluent gradient to obtain 6-amino-3-bromo-2-methylbenzonitrile (brown solid, 2.3 g, 72.0%). MS (ESI + )m / z = 210.9 [M-H] - .

[0325] Preparation of Intermediate 7. 2-amino-5-bromo-4-fluorobenzonitrile

[0326] Dissolve 2-amino-4-fluorobenzonitrile (2.0 g, 14.69 mmol) in acetic acid (20 mL), add NBS (2.6 g, 14.69 mmol), and stir at 70 °C for 2 h. After the reaction is completed, cool to room temperature, add water (15 mL) to the reaction solution, extract the mixture with ethyl acetate (40 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate the resulting residue by silica gel column chromatography using ethyl acetate / petroleum ether (0-40%) as the eluent gradient to obtain 2-amino-5-bromo-4-fluorobenzonitrile (brown solid, 2.3 g, 72.8%). MS (ESI + )m / z = 212.9 [M-H] - .

[0327] Preparation of Intermediate 8. 8-bromo-6-nitroquinazolin-4-amine

[0328] Dissolve 2-amino-3-bromo-5-nitrobenzonitrile (3.0 g, 12.40 mmol) in ethylene glycol monomethyl ether (20 mL) under nitrogen protection, and add formamidine acetate (6.5 g, 61.98 mmol). Stir at 130 °C for 3 h. After the reaction is completed, cool to room temperature, add water to the reaction solution, and extract the mixture with ethyl acetate (40 mL x 3). Dry the combined organic phases over anhydrous sodium sulfate, filter, and dry the filter cake to obtain 8-bromo-6-nitroquinazolin-4-amine (yellow solid, 2.2 g, 66.0%). MS (ESI + )m / z = 269.1 [M+H] + .

[0329] Preparation of Intermediate 9. 1-(6-amino-3-bromo-2-fluorophenyl)ethanone

[0330] To a stirred solution of 1-(2-amino-6-fluorophenyl)ethanone (2.0 g, 13.06 mmol) in DMF (20 mL) was added NBS (2.3 g, 13.06 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate in petroleum ether (0-40%) as eluent to afford 1-(6-amino-3-bromo-2-fluorophenyl)ethanone (brown solid, 2.3 g, 76.2%). MS (ESI + m / z = 232.0 [M+H] + .

[0331] Preparation of intermediate 10. 8-bromo-6-chloropyrido[3,4-d]pyrimidin-4-amine

[0332] First step: To a stirred solution of 3-aminonicotinonitrile (2.0 g, 16.79 mmol) in DMF (20 mL) was added NCS (2.2 g, 16.79 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by column chromatography on C18 using acetonitrile in water (0-100%) as eluent to afford 5-amino-2-chloronicotinonitrile (colorless transparent oil, 850 mg, 33.0%). MS (ESI + m / z = 154.1 [M+H] + .

[0333] Second to fourth steps: 8-bromo-6-chloropyrido[3,4-d]pyrimidin-4-amine (yellow oil, 150 mg, 66.5%) was prepared following the procedure described in the third to fifth steps of the synthesis of intermediate Al l using 5-amino-2-chloronicotinonitrile as the starting material. MS (ESI + m / z = 260.9 [M+H] + .

[0334] Preparation of intermediate 11. 4-chloro-6-methylpyrimidine-5-carboxylic acid ethyl ester

[0335] Step 1: 2-(1-ethoxyethyl)propanedioic acid diethyl ester (4.5 g, 19.54 mmol) was dissolved in ethanol (50 mL), and then methylformamidine (3.1 g, 29.31 mmol) and potassium tert-butoxide (4.4 g, 39.09 mmol) were added successively. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography using methanol / dichloromethane (5%) as the eluent to obtain 4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid ethyl ester (yellow solid, 2.6 g, 73.0%). MS (ESI + m / z = 183.1 [M+H] + .

[0336] Step 2: 4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid ethyl ester (2.6 g, 14.27 mmol) was dissolved in DCM (30 mL), and then DMF (521.6 mg, 7.14 mmol) and oxalyl chloride (2.7 g, 21.41 mmol) were added successively. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was cooled to 0°C, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (50%) as the eluent to obtain 4-chloro-6-methylpyrimidine-5-carboxylic acid ethyl ester (yellow oil, 1 g, 35.0%). MS (ESI + m / z = 201.1 [M+H] + .

[0337] Preparation of Intermediate 12. 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid

[0338] tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (5.0 g, 18.43 mmol) was dissolved in a THF / MeOH and H2O mixture (1 / 1 / 1 v / v / v, 20 mL), and then LiOH (2.2 g, 92.13 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The aqueous phase was adjusted to pH 3 with hydrochloric acid (1M), extracted with dichloromethane (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (white solid, 4.3 g, 96.0%). MS (ESI + m / z = 242.1 [M-H] - .

[0339] Preparation of Intermediate 13. 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid

[0340] First Step: tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperidine-l-carboxylate (5.0 g, 18.43 mmol) was dissolved in THF (50 mL) under nitrogen protection, and the solution was cooled to -78 °C. LiHMDS in THF (1 M, 36.9 mL, 36.85 mmol) was added in sequence, and the mixture was stirred at -78 °C for 1 h. Iodomethane (3.1 g, 22.11 mmol) was added, and the mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed, water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(l-ethoxy-l-oxopropan-2-yl)piperidine-l-carboxylate (yellow oil, 4.3 g, crude).

[0341] Second Step: 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (white solid, 1.5 g, 31.9% yield over two steps) was prepared from tert-butyl 4-(l-ethoxy-l-oxopropan-2-yl)piperidine-l-carboxylate (4.3 g, 15.07 mmol) according to the procedure described for the synthesis of Intermediate 12. MS (ESI + m / z = 256.2 [M-H] - .

[0342] Preparation of Intermediate 14. tert-Butyl (lR,5S)-3-chloro-8-azabicyclo[3.2.1]octane-8- carboxylate

[0343] (1R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 8.80 mmol) was dissolved in THF (20 mL) under nitrogen protection, and PPh3 (4.6 g, 17.60 mmol) and CC14 (2.7 g, 17.60 mmol) were added in sequence. The mixture was stirred at 50 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (10%) as the eluent to give tert-butyl (lR,5S)-3-chloro-8-azabicyclo[3.2.1]octane-8-carboxylate (white solid, 1.3 g, 60.2%). MS (ESI + m / z = 190.1 [M+H-56] + .

[0344] Preparation of Intermediate 15. 6-bromo-8-iodo-4-methylquinazoline

[0345] First Step: 1-(2-amino-5-bromophenyl)ethanone (3.0 g, 14.01 mmol) was dissolved in acetic acid (40 mL), cooled to 0 °C, and NIS (3.5 g, 15.42 mmol) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, water (200 mL) was added to the reaction mixture, and a solid was precipitated. The solid was collected by filtration, and dried to give 1-(2-amino-5-bromo-3-iodophenyl)ethanone (yellow solid, 4.5 g, 94.4%). MS (ESI) m / z = 339.9 [M+H] + m / z = 339.9 [M+H] + .

[0346] Second Step: 1-(2-amino-5-bromo-3-iodophenyl)ethanone (8.0 g, 23.53 mmol) was dissolved in methanol (80 mL) under nitrogen protection, and ammonium acetate (3.6 g, 47.06 mmol), copper chloride dihydrate (802.4 mg, 4.71 mmol), and TBHP (12.7 g, 141.19 mmol) were added successively. The reaction was stirred at 60 °C for 5 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-72%) as the eluent to give 6-bromo-8-iodo-4-methylquinazoline (yellow solid, 3.5 g, 42.6%). MS (ESI) m / z = 348.9 [M+H] + m / z = 348.9 [M+H] + .

[0347] Preparation of Intermediates A1-A24 in the second group of preparation examples

[0348] Preparation of Intermediate A1. tert-Butyl 5-(4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0349] Step 1: N'-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (2.0 g, 6.35 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. NaH (639.8 mg, 15.99 mmol, 60%) was added portionwise while maintaining the temperature at 0 °C and stirred for 0.5 h. p-Toluenesulfonyl chloride (1.5 g, 7.62 mmol) was added. The temperature was raised to room temperature and stirred for 0.5 h. After the reaction was completed, ice water (20 mL) was added slowly and a solid precipitated. The solid was filtered and the filter cake was washed with water (50 mL x 3) and then dissolved in ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 5) as the eluent to obtain N'-(5-iodo-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (brown solid, 2.2 g, 72.6%). MS (ESI + m / z = 470.0 [M+H] + .

[0350] Step 2: N'-(5-iodo-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (1.0 g, 2.13 mmol) was dissolved in a mixture of 1,4-dioxane and water (12.5 mL, 4 / 1 v / v) under nitrogen protection. Pd(dppf)Cl2·CH2Cl2(174.0 mg, 0.21 mmol), 1-BOC-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (989.3 mg, 3.19 mmol), and potassium carbonate (883.5 mg, 6.39 mmol) were added in sequence. The temperature was raised to 100 °C and stirred for 5 h. After the reaction was completed, the temperature was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 2-1 / 1) as the eluent gradient to obtain 5-(4-(((dimethylamino)methylene)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (brown solid, 820 mg, 73.2%). MS (ESI + m / z = 525.2 [M+H] + .

[0351] Third step: Dissolve 5-(4-(((dimethylamino)methylene)amino)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 3.05 mmol) in THF (16 mL), add TBAF tetrahydrofuran solution (1 M, 12.2 mL, 12.20 mmol) portionwise. Warm to 50 °C and stir for 3 h. After complete reaction, cool to room temperature and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 1→2 / 1) gradient to give 5-(4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (brown solid, 800 mg, 70.9%). MS (ESI + m / z = 371.2 [M+H] + .

[0352] Preparation of Intermediate A2. tert-Butyl 3-(4-(((dimethylamino)methylene)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[0353] Dissolve tert-butyl 5-(4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-3,6-dihydropyridine-1(2H)-carboxylate (500.0 mg, 0.22 mmol) in MeOH (20 mL) under nitrogen protection, add Pd / C (700 mg, 100% m / m). Replace hydrogen gas, warm to 65 °C and stir overnight. After complete reaction, cool to room temperature, filter and concentrate the filtrate under reduced pressure to give tert-butyl 3-(4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1- carboxylate. MS (ESI + m / z = 373.2 [M+H] + .

[0354] Preparation of Intermediate A3. tert-Butyl 5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate

[0355] Prepare Intermediate A3 from 5-iodo-7H-pyrrolo[2,3-d]pyrimidine following the procedure described for Intermediate Al.

[0356] MS (ESI + m / z = 301.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.24 (s, 1H), 8.76 (s, 1H), 7.63 (s, 1H), 6.42 (s, 1H), 4.22 (d, J = 1.7 Hz, 2H), 3.50 (t, J = 5.6 Hz, 2H), 2.34 - 2.23 (m, 2H), 1.44 (s, 9H).

[0357] Preparation of Intermediate A4. tert-Butyl 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3,6-dihydropyridine-1(2H)-carboxylate

[0358] Intermediate A4 was prepared from 4-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine following the procedure for the synthesis of Intermediate Al. MS (ESI + )m / z = 319.2 [M+H] + .

[0359] Preparation of Intermediate A5. tert-Butyl 3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)piperidine-1-carboxylate

[0360] Intermediate A5 was prepared from Intermediate A4 following the procedure for the synthesis of Intermediate A2. MS (ESI + )m / z = 317.2 [M+H] + .

[0361] Preparation of Intermediate A6. tert-Butyl 5-(4-((4-methoxybenzyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate

[0362] Step 1: Under nitrogen protection, 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 35.85 mmol) was dissolved in DMF (150 mL), and cooled to 0 °C. NaH (1.1 g, 46.61 mmol) was added, and stirred at 0 °C for 0.5 h. Then p-toluenesulfonyl chloride (10.3 g, 53.78 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 h. After the reaction was completed, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel with ethyl acetate / petroleum ether (0-28%) as eluent to give 4-chloro-5-iodo-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine (yellow solid, 13.7 g, 90.2%). MS (ESI) m / z = 433.9 [M+H] + . + .

[0363] Step 2: Under nitrogen protection, 4-chloro-5-iodo-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 13.84 mmol) was dissolved in 1,4-dioxane (100 mL), and Pd2(dba)3 (1.3 g, 1.38 mmol), Xphos (659.6 mg, 1.38 mmol), triethylamine (7.0 g, 69.18 mmol) and pinacol borane (7.1 g, 55.34 mmol) were added successively. The reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel with ethyl acetate / petroleum ether (0-40%) as eluent to give 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine (yellow oil, 3 g, 50.0%). MS (ESI) m / z = 434.1 [M+H] + . + .

[0364] Step 3: Under nitrogen, 4-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7- p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 3.46 mmol) was dissolved in 1,4- dioxane (20 mL), followed by the addition of DIEA (894.0 mg, 6.92 mmol) and (4- methoxyphenyl)methanamine (711.7 mg, 5.19 mmol), and the mixture was stirred at 120 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to give N-(4- methoxybenzyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7-p-tolylsulfonyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine (yellow solid, 1.8 g, crude). MS (ESI + m / z = 535.2 [M+H] + .

[0365] Step 4: Under nitrogen, tert-butyl 2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-l(2H)-carboxylate (1.0 g, 2.90 mmol) was dissolved in a mixture of 1,4- dioxane and water (10 / 1 v / v, 11 mL), followed by the addition of N-(4-methoxybenzyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin- 4-amine (1.9 g, 3.47 mmol), Pd(dppf)Cl2-CH2Cl2(211.9 mg, 0.29 mmol), and K2CO3(1.2 g, 8.69 mmol), and the mixture was stirred at 100 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-100%) as eluent to give tert-butyl 5-(4-((4-methoxybenzyl)amino)-7-p-tolylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 2-methyl-3,6-dihydropyridine-l(2H)-carboxylate (yellow solid, 1.2 g, 68.6%). MS (ESI + m / z = 604.4 [M+H] + .

[0366] Fifth step: tert-Butyl 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-methyl-3,6-dihydropyridine-1 (2H)-carboxylate (1.2 g, 1.99 mmol) was dissolved in methanol (20 mL) under nitrogen, K2CO3(549.4 mg, 3.98 mmol) was added, and the mixture was stirred at 60 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-methyl-3,6-dihydropyridine-1 (2H)-carboxylate (yellowish solid, 750 mg, 83.9%). MS (ESI + m / z = 450.3 [M+H] + .

[0367] Sixth step: tert-Butyl 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-methyl-3,6-dihydropyridine-1 (2H)-carboxylate (750.0 mg, 1.67 mmol) was dissolved in ethanol (20 mL), and ammonium formate (1.1 g, 16.68 mmol) and Pd / C (10%, 1.8 g, 16.68 mmol) were added successively. The mixture was stirred at 60 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and filtered with celite. The filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate (white solid, 440 mg, 58.4%). MS (ESI + m / z = 452.4 [M+H] + .

[0368] Preparation of Intermediate A7. tert-Butyl 2-methyl-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)piperidine-1-carboxylate

[0369] Step 1: Under nitrogen protection, 5-iodo-4-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.26 mmol) was dissolved in a mixture of DMF and water (10 / 1 v / v, 30 mL). Then, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.6 g, 7.99 mmol), Pd(dppf)Cl2·CH2Cl2 (592.9 mg, 0.73 mmol), and K2CO3 (3.0 g, 21.78 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 2 h. After the reaction was complete and cooled to room temperature, saturated saline solution (35 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-100%) to obtain tert-butyl 2-methyl-5-(4-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yellow solid, 2 g, 57.1%). MS (ESI) + m / z = 483.4 [M+H] + .

[0370] Step 2: Under nitrogen protection, 2-methyl-5-(4-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.0 g, 4.14 mmol) was dissolved in THF (20 mL), and TBAF (2.2 g, 8.29 mmol) was added. The mixture was heated to 60 °C and stirred for 4 h. After the reaction was complete and cooled to room temperature, saturated brine (20 mL) was added to the reaction solution. 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. The residue was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-100%) to obtain tert-butyl 2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yellow solid, 1.35 g, 99.2%). MS (ESI) + m / z = 329.2[M+H] + .

[0371] Step 3: tert-Butyl 2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine- 1 (2H)-carboxylate (1.4 g, 4.26 mmol) was used as the starting material to prepare tert-Butyl 2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1- carboxylate (brown oil, 800 mg, 56.8%) according to the method of the sixth step of the synthesis of Intermediate A6. MS (ESI + )m / z = 331.1 [M+H] + .

[0372] Preparation of tert-Butyl 4-((4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidine- 1-carboxylate

[0373] Step 1: 5-Iodo-4-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.42 mmol) was dissolved in a mixture of EtOH, H2O and DCE (3 / 4 / 12 v / v / v, 19 mL), and tert-Butyl 4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl)piperidine-l-carboxylate (938.6 mg, 2.90 mmol), Pd(PPh3)4 (139.8 mg, 0.12 mmol) and Na2CO3 (1.0 g, 9.68 mmol) were added successively. The reaction mixture was stirred at 120 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel with ethyl acetate / petroleum ether (50%) as the eluent to give tert-Butyl 4-((4-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidine-l-carboxylate (yellow oil, 870 mg, 74.5%). MS (ESI + )m / z = 483.2 [M+H] + .

[0374] Second Step: tert-Butyl 4-((4-methyl-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (870.0 mg, 1.80 mmol) was dissolved in methanol (10 mL) under nitrogen protection, Pd / C (435.0 mg) was added, and hydrogen was replaced. After stirring at room temperature overnight, the reaction was complete. The reaction solution was filtered with diatomite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-((4-methyl-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (yellow solid, 700 mg, crude). MS (ESI + m / z = 485.2 [M+H] + .

[0375] Third Step: tert-Butyl 4-((4-methyl-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (700.0 mg, 1.44 mmol) was dissolved in THF (10 mL), and TBAF THF solution (1 M, 5.8 mL, 5.78 mmol) was added. After stirring at reflux for 4 h, the reaction was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (50%) as the eluent to obtain tert-butyl 4-((4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (yellow solid, 400 mg, 67.2% yield for two steps). MS (ESI + m / z = 331.2 [M+H] + .

[0376] Preparation of Intermediate A9. tert-Butyl 3-(4-((4-methoxybenzyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate

[0377] tert-Butyl 3-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1- carboxylate was prepared from N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and tert- butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate according to the method for preparing Intermediate A6, fourth to sixth steps.

[0378] Preparation of Intermediate A10. tert-Butyl 3-(4-((4-methoxybenzyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl-6-d)piperidine-1-carboxylate

[0379] Step 1 : 4-Chloro-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 19.50 mmol) was dissolved in THF (40 mL) under nitrogen, cooled to -78 °C, and LDA (2 M in THF, 17.5 mL, 35.09 mmol) and I2 (20 mL, 6.4 g, 25.35 mmol) were added sequentially. The mixture was stirred at -78 °C for 2 h. After the reaction was completed, HCl (1 M, 35 mL) was added to the reaction mixture, which was allowed to warm to room temperature. The mixture was extracted with dichloromethane (200 mL x 3), and the combined organic layers were washed with water (120 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (0-30%) as eluent to give 4-chloro-6-iodo-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (yellow solid, 3 g, 35.5%). MS (ESI) m / z = 433.9 [M+H] + m / z = 279.9 [M+H] + .

[0380] Step 2: 4-Chloro-6-iodo-7-(p-tolylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 6.92 mmol) was dissolved in methanol (20 mL), and K2CO3 (4.8 g, 34.59 mmol) was added. The mixture was stirred at 60 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (150 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (0-40%) as eluent to give 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (yellow solid, 1.4 g, 72.4%). MS (ESI) m / z = 279.9 [M+H] + m / z = 279.9 [M+H] + .

[0381] Step 3: 4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 5.01 mmol) was dissolved in 1,4-dioxane (20 mL), (4-methoxyphenyl)methanamine (893.4 mg, 6.51 mmol) and DIEA (1.9 g, 15.03 mmol) were added successively, and the mixture was stirred at 120 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with water (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-90%) as eluent to give 6-iodo-N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yellow solid, 1.7 g, 89.3%). MS (ESI) m / z = 381.0 [M+H] + . + .

[0382] Step 4: 6-Iodo-N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.7 g, 4.47 mmol) was dissolved in deuterated acetic acid (5 mL), and zinc powder (850.2 mg, 13.41 mmol) was added. The mixture was stirred at room temperature for 18 h. After the reaction was completed, the mixture was filtered, and sodium bicarbonate aqueous solution (1 M, 50 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-50%) as eluent to give N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-d-4-amine (yellow solid, 900 mg, 78.8%). MS (ESI) m / z = 256.1 [M+H] + . + .

[0383] Step 5: Dissolve N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-d-4-amine (900.0 mg, 3.53 mmol) in DMF (5 mL), add NBS (627.4 mg, 3.53 mmol), and warm to 40 °C for 2 h. After the reaction is complete, cool to room temperature, add saturated aqueous sodium chloride solution (50 mL) to the reaction, extract the mixture with ethyl acetate (50 mL x 3), combine the organic layers, wash with water (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography eluting with ethyl acetate / petroleum ether (0-50%) to give 5-bromo-N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-d-4-amine (yellow solid, 450 mg, 38.2%). MS (ESI) m / z = 334.0 [M+H] + m / z = 334.0 [M+H] + .

[0384] Step 6: Dissolve 5-bromo-N-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-d-4-amine (300.0 mg, 0.90 mmol) in a mixture of 1,4-dioxane and water (10 / 1 v / v, 11 mL), add dichlorobis(tricyclohexylphosphine)palladium (66.3 mg, 0.090 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (416.4 mg, 1.35 mmol), and potassium carbonate (248.1 mg, 1.80 mmol) sequentially, and warm to 100 °C for 2 h. After the reaction is complete, cool to room temperature, add water (100 mL) to the reaction, extract the mixture with ethyl acetate (50 mL x 3), combine the organic layers, wash with water (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography eluting with ethyl acetate / petroleum ether (0-50%) to give 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl-6-d)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (yellow solid, 200 mg, 51.0%). MS (ESI) m / z = 437.2 [M+H] + m / z = 437.2 [M+H] + .

[0385] Seventh step: tert-butyl 3-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl-6-d)-piperidine-1-carboxylate (200.0 mg, 0.46 mmol) was dissolved in methanol (5 mL) under nitrogen protection, Pd / C (10%, 1 g) was added, hydrogen was replaced, and the temperature was raised to 40 °C for stirring for 1 h. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl-6-d)piperidine-1-carboxylate (yellow solid, 95 mg, 47.3%). MS (ESI + )m / z = 439.3 [M+H] + .

[0386] Preparation of intermediate A11. tert-butyl 3-(4-amino-8-bromoquinazolin-6-yl)piperidine-1-carboxylate

[0387] First step: 2-amino-5-bromobenzonitrile (2.0 g, 10.15 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 22 mL), Pd(dppf)Cl2·CH2Cl2(828.9 mg, 1.02 mmol) and K2CO3(4.2 g, 30.45 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.7 g, 15.23 mmol) were added in turn, and the temperature was raised to 100 °C for stirring for 1 h. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (70 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient to obtain tert-butyl 5-(4-amino-3-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (white solid, 3 g, 98.7%). MS (ESI + )m / z = 244.1 [M+H-56] + .

[0388] Second Step: tert-Butyl 5-(4-amino-3-cyanophenyl)-3,6-dihydropyridine-1 (2H)- carboxylate (2.0 g, 6.68 mmol) was dissolved in methanol (40 mL) under nitrogen protection, Pd / C (2.1 g, 20.04 mmol) was added, and hydrogen was replaced. After stirring at room temperature for 2 h, the reaction was complete. The reaction solution was filtered with diatomite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(4-amino-3-cyanophenyl)piperidine-1-carboxylate (yellow solid, 1.9 g, crude). MS (ESI + )m / z = 324.2 [M+Na] + .

[0389] Third Step: tert-Butyl 3-(4-amino-3-cyanophenyl)piperidine-1-carboxylate (1.9 g, 6.30 mmol) was dissolved in methanol (20.0 mL), and the temperature was lowered to 0 °C. Pyridinium tribromide (3.3 g, 9.46 mmol) was added, and the temperature was restored to room temperature. After stirring for 1 h, the reaction was complete. Water (70 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent gradient to obtain tert-butyl 3-(4-amino-3-bromo-5-cyanophenyl)piperidine-1-carboxylate (yellow solid, 1.3 g, 54.2%). MS (ESI + )m / z = 365.1 [M+H-15] + .

[0390] Fourth Step: tert-Butyl 3-(4-amino-3-bromo-5-cyanophenyl)piperidine-1-carboxylate (1.3 g, 3.42 mmol) was dissolved in DMF-DMA (15 mL), and the temperature was raised to 100 °C. After stirring for 1 h, the reaction was complete. The temperature was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain tert-butyl 3-(3-bromo-5-cyan-4-(((dimethylamino)methylene)amino)phenyl)piperidine-1-carboxylate (yellow solid, 1.5 g, crude). MS (ESI + )m / z = 435.2 [M+H] + .

[0391] Fifth step: tert-butyl 3-(3-bromo-5-cyano-4-(((dimethylamino)methylene)amino) phenyl)piperidine-1-carboxylate (1.5 g, 3.45 mmol) was dissolved in acetic acid (4 mL), ammonium acetate (478.0 mg, 6.20 mmol) was added, and the mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (0-10%) as the eluent to give tert-butyl 3-(4-amino-8-bromoquinazolin-6-yl)piperidine-1-carboxylate (yellow solid, 800 mg, 57.0%). MS (ESI + )m / z = 407.2 [M+H] + .

[0392] Preparation of intermediates A12-A17

[0393] Intermediates A12-A17 were prepared using the preparation method of intermediate A11 described above, using a substituted cyanophenylamine compound prepared or commercially available and boron ester as raw materials. See Table 1 for details.

[0394] Table 1. Structures, characterization data and starting materials of intermediates A12-A17

[0395] Preparation of intermediate A18, tert-butyl 4-(4-amino-3,5-dibromo phenyl)piperazine-1-carboxylate

[0396] First step: 1,3-dibromo-5-fluoro-2-nitrobenzene (1.1 g, 3.71 mmol) was dissolved in DMSO (10 mL) under nitrogen protection, and tert-butyl piperazine-1-carboxylate (690.2 mg, 3.71 mmol) and K2CO3 (1.0 g, 7.41 mmol) were added in sequence. The mixture was stirred at 100 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (0-10%) as the eluent to give tert-butyl 4-(3,5-dibromo-4-nitrophenyl)piperazine-1-carboxylate (yellow oil, 1.5 g, 87.0%). MS (ESI + )m / z = 451.0 [M+H] + .

[0397] Second Step: tert-Butyl 4-(3, 5-dibromo-4-nitrophenyl)piperazine-1 -carboxylate (1.0 g, 2.15 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, 4,4'-dipyridine (1.0 g, 6.45 mmol) and tetrahydroxydiboron (57.8 mg, 0.64 mmol) were added, and the reaction was stirred at room temperature for 20 min. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent to give tert-butyl 4-(4-amino-3, 5-dibromophenyl)piperazine-1 -carboxylate (yellow solid, 900 mg, 96.8%). MS (ESI + )m / z = 436.0 [M+H] + .

[0398] Preparation of Intermediate A19. tert-Butyl 3-(4-amino-8-bromoquinazolin-6-yl)azetidine-1 -carboxylate

[0399] First Step: 2-Amino-5-bromobenzonitrile (2.0 g, 10.15 mmol) was dissolved in THF (20 mL) under nitrogen protection, and Pd2(dba)3(464.7 mg, 0.51 mmol), Pd(t-Bu3P)2(1.0 g, 2.03 mmol) and (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc iodide (Intermediate 4, 5.0 g, 14.21 mmol) were added in turn. The reaction was stirred at 90 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to give tert-butyl 3-(4-amino-3-cyanophenyl)azetidine-1 -carboxylate (brown solid, 1.1 g, 39.6%). MS (ESI + )m / z = 272.2 [M-H] - .

[0400] Second to Fourth Steps: tert-Butyl 3-(4-amino-8-bromoquinazolin-6-yl)azetidine-1 -carboxylate (yellow oil) was prepared from tert-butyl 3-(4-amino-3-cyanophenyl)azetidine-1 -carboxylate according to the method of the third to fifth steps of the synthesis of Intermediate A11. MS (ESI + )m / z = 381.0 [M+H] + .

[0401] Preparation of Intermediate A20. tert-Butyl 3-(8-bromo-4-methylquinazolin-6- yl)piperidine-1 -carboxylate

[0402] First Step: tert-Butyl 5-(3-acetyl-4-aminophenyl)-3,6-dihydropyridine-1 (2H)- carboxylate (4.0 g, 18.69 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 11 mL) under nitrogen protection, Pd(dppf)Cl2CH2Cl2(1.5 g, 1.87 mmol), Cs2CO3(18.3 g, 56.06 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1 (2H)-carboxylate (5.1 g, 28.03 mmol) were added successively, and the mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and saturated aqueous NaCl solution (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (60 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using ethyl acetate / petroleum ether (0-20%) as the eluent to give tert-butyl 5-(3-acetyl-4-aminophenyl)-3,6-dihydropyridine-1 (2H)-carboxylate (yellow solid, 4.5 g, 76.1 %). MS (ESI) m / z = 317.2 [M+H] + )m / z = 317.2 [M+H] + .

[0403] Second Step, Third Step: tert-Butyl 3-(3-acetyl-4-amino-5-bromophenyl)piperidine-1 - carboxylate (yellow solid) was prepared from tert-butyl 5-(3-acetyl-4-aminophenyl)-3,6- dihydropyridine-1 (2H)-carboxylate according to the method of the second step and the third step of the synthesis of Intermediate A11. + )m / z = 317.2 [M+H] + .

[0404] Fourth Step: tert-Butyl 3-(8-bromo-4-methylquinazolin-6-yl)piperidine-1 -carboxylate (yellow solid, 800 mg, 60.2%) was prepared from tert-butyl 3-(3-acetyl-4-amino-5- bromophenyl)piperidine-1 -carboxylate according to the method of the fourth step of the synthesis of Intermediate A20. MS (ESI) m / z = 341.0 [M+H-56]+ m / z = 406.1 [M+H] + .

[0405] Preparation of intermediate A21. tert-Butyl 4-(8-bromo-4-methylquinazolin-6- yl)piperidine-1-carboxylate

[0406] First to third steps: tert-Butyl 4-(3-acetyl-4-amino-5-bromophenyl)piperidine-1- carboxylate (yellow solid) was prepared from 1-(2-amino-5-bromophenyl)ethanone, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate and pyridinium tribromide, following the procedures for the first to third steps of the synthesis of intermediate A11. MS (ESI + m / z = 341.1 [M+H-56] + .

[0407] Fourth step: tert-Butyl 4-(3-acetyl-4-amino-5-bromophenyl)piperidine-1-carboxylate (1.0 g, 2.52 mmol) was dissolved in methanol (30 mL) under nitrogen protection, and ammonium acetate (388.0 mg, 5.03 mmol) and anhydrous copper chloride (67.7 mg, 0.50 mmol) were added successively, followed by dropwise addition of TBHP in heptane (5.5 M 70%, 4.6 mL, 17.62 mmol). The reaction was stirred at 60 °C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient, and then separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-100%) as eluent gradient to give tert-butyl 4-(8-bromo-4-methylquinazolin-6-yl)piperidine-1-carboxylate (pale yellow solid, 1 g, 97.8%). MS (ESI + m / z = 408.0 [M+H] + .

[0408] Preparation of intermediates A22-A24

[0409] Intermediates A22-A24 were prepared from the preparation or commercially available boron ester and the preparation or commercially available substituted aminoacetophenone compound, following the preparation method of intermediate A21, as shown in Table 2. The first step coupling condition can also be: Pd(dppf)Cl2·CH2Cl2, K2CO3, DMF, H2O, 100 °C or Pd(dppf)Cl2·CH2Cl2, Cs2CO3, 1,4-dioxane, H2O, 100 °C. The second step reduction condition can also be: Pd / C, HCOONH4, MeOH, 60 °C

[0410] Table 2. Structures, characterization data and starting materials of intermediates A22-A24

[0411] Preparation of intermediates B1-B9

[0412] Preparation of intermediate B1. tert-Butyl 2-(2,2-dicyano-1-methoxyvinyl)morpholine-4- carboxylate

[0413] First step: 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (9.8 g, 42.38 mmol) was dissolved in toluene (100 mL) under nitrogen protection, and the solution was cooled to 0 °C. Oxalyl chloride (5.4 g, 42.38 mmol) was added dropwise slowly, and then DMF (4 mL) was added dropwise slowly. The mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was warmed to room temperature, and DCM (20 mL) was added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was used directly in the next step without purification.

[0414] Propiolonitrile (2.0 g, 29.66 mmol) was dissolved in THF (40 mL) under nitrogen protection, and the solution was cooled to 0 °C. NaH (2.4 g, 59.33 mmol, 60%) was added portionwise, and the mixture was stirred at 0 °C for 10 min. The DCM (20 mL) solution of the crude product was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with methanol / dichloromethane (1 / 10) as the eluent to give tert-butyl 2-(2,2-dicyano-1-hydroxyvinyl)morpholine-4-carboxylate (yellow oil, 4 g, 33.8%). MS (ESI + )m / z = 277.9 [M-H] - .

[0415] Second step: tert-Butyl 2-(2,2-dicyano-1-hydroxyvinyl)morpholine-4-carboxylate (3.5 g, 12.53 mmol) was dissolved in THF (40 mL) under nitrogen protection, and the solution was cooled to -78 °C. A solution of TMSCHN2 in n-hexane (1 M, 6.3 mL, 6.27 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 1) as the eluent to give tert-butyl 2-(2,2-dicyano-1-methoxyvinyl)morpholine-4-carboxylate (yellow oil, 2 g, 54.4%). MS (ESI + )m / z = 292.1 [M-H] - .

[0416] Preparation of Intermediate B2. tert-Butyl 3-(2,2-dicyano-l-methoxyvinyl)piperidine-l- carboxylate

[0417] Under nitrogen protection, 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.0 g, 4.36 mmol) was dissolved in toluene (10.0 mL), cooled to 0 °C, oxalyl chloride (554.0 mg, 4.36 mmol) was added dropwise slowly, then DMF (0.4 mL) was added dropwise slowly, stirred at 0 °C for 2 h, after the reaction was completed, it was warmed to room temperature, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain a crude product (brown oil). No purification was needed, and it was directly used in the next step.

[0418] Under nitrogen protection, malononitrile (202.0 mg, 3.05 mmol) was dissolved in THF (10.0 mL), cooled to 0 °C, NaH (244.0 mg, 6.11 mmol, 60%) was added in portions, and stirred at 0 °C for 10 min. A DCM (5 mL) solution of the above crude product was added dropwise, and stirred at room temperature for 1 h. Then dimethyl sulfate (462 mg, 3.66 mmol) was added, heated to reflux and stirred overnight. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added slowly, extracted with EtOAc (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 10) as the eluent to obtain tert-butyl 3-(2,2-dicyano-l-methoxyvinyl)piperidine-l-carboxylate (yellow oil, 250.0 mg, three-step yield: 19.7%).

[0419] MS (ESI + )m / z = 290.1 [M-H] - . 1 H NMR (300 MHz, DMSO-d6) δ 4.31 (s, 3H), 4.04 - 3.93 (m, 1H), 3.85 (d, J = 12.9 Hz, 1H), 2.78 (ddd, J = 14.0, 10.5, 7.8 Hz, 3H), 1.88 (d, J = 10.4 Hz, 1H), 1.64 (ddd, J = 15.0, 8.4, 2.7 Hz, 3H), 1.40 (s, 9H).

[0420] Preparation of Intermediate B3. Benzyl 5-(2,2-dicyano-l-methoxyvinyl)-2- (methoxymethyl)piperidine-l-carboxylate

[0421] First step: 6-hydroxymethylnicotinic acid methyl ester (10.0 g, 59.8 mmol) was dissolved in DCM (100 mL), cooled to 0 °C, and thionyl chloride (10.7 g, 89.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (100 mL), and sodium methoxide in methanol (1 M, 120 mL, 119.6 mmol) was added. The mixture was stirred at 70 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (200 mL) was added, and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (1 / 5) as the eluent to give 6-(methoxymethyl)nicotinic acid methyl ester (yellow solid, 5.3 g, 49.1%). MS (ESI + )m / z = 182.2 [M+H] + .

[0422] Second step: 6-(Methoxymethyl)nicotinic acid methyl ester (4.3 g, 23.7 mmol) was dissolved in methanol (40 mL) and acetic acid (4 mL) under nitrogen protection. Platinum dioxide (2.7 g, 11.9 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude 6-(methoxymethyl)piperidine-3-carboxylic acid methyl ester (brown oil, 7.0 g, crude), which was used directly in the next step without purification. MS (ESI + )m / z = 188.2 [M+H] + .

[0423] Third step: 6-(Methoxymethyl)piperidine-3-carboxylic acid methyl ester (7.0 g, 37.4 mmol) was dissolved in DCM (70 mL) under nitrogen protection. DIEA (9.7 g, 74.8 mmol) was added, and the mixture was cooled to 0 °C. CbzCl (7.7 g, 44.9 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added. The mixture was extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate / petroleum ether (1 / 10) as the eluent to give 3-methyl-6-(methoxymethyl)piperidine-1,3-dicarboxylic acid 1-benzyl ester (colorless oil, 2.7 g, crude), which was used directly in the next step without purification. MS (ESI + )m / z = 322.2 [M+H] + .

[0424] Fourth Step: Dissolve 3-methyl-6-(methoxymethyl)piperidine-1,3-dicarboxylic acid-1- benzyl ester (2.7 g, 8.4 mmol) in a mixture of tetrahydrofuran / methanol / water (30 mL, 1 / 1 / 1 v / v / v), add lithium hydroxide (1.8 g, 42.0 mmol), stir at room temperature for 1 h, after the reaction is completed, concentrate under reduced pressure, add DCM (20 mL), adjust pH to 2 with hydrochloric acid (1 M), separate the phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by separation on a reverse-phase column using H2O / acetonitrile (3 / 2) as the eluent to obtain 1-((benzyloxy)carbonyl)-6-(methoxymethyl)piperidine-3-carboxylic acid (white solid, 1.6 g, three-step yield: 21.9%). MS (ESI + m / z = 308.2 [M+H] + .

[0425] Fifth Step: Dissolve 1-((benzyloxy)carbonyl)-6-(methoxymethyl)piperidine-3-carboxylic acid (1.6 g, 5.2 mmol) in DCM (15 mL), add EDCI . HCl (1.2 g, 6.2 mmol), HOBT (838.0 mg, 6.2 mmol), and TEA (1.1 g, 10.4 mmol), stir at room temperature for 0.5 h, add malononitrile (409.0 mg, 6.2 mmol), continue stirring at room temperature for 1 h, after the reaction is completed, add water (20 mL), extract with DCM (10 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by chromatography on a silica gel column using ethyl acetate / petroleum ether (1 / 1) as the eluent to obtain benzyl 5-(2,2-dicyano-1-hydroxyvinyl)-2-(methoxymethyl)piperidine-1-carboxylate (yellow oil, 1.1 g, 59.5%). MS (ESI + m / z = 354.1 [M+H] + .

[0426] Sixth Step: Dissolve benzyl 5-(2,2-dicyano-1-hydroxyvinyl)-2-(methoxymethyl)piperidine-1- carboxylate (1.0 g, 2.8 mmol) in orthoformic acid trimethyl ester (10 mL), heat to 100 °C and stir for 1 h. After the reaction is completed, concentrate under reduced pressure, and purify by chromatography on a silica gel column using ethyl acetate / petroleum ether (1 / 1) as the eluent to obtain benzyl 5-(2,2-dicyano-1-methoxyvinyl)-2-(methoxymethyl)piperidine-1-carboxylate (yellow oil, 600.0 mg, 57.7%). MS (ESI + m / z = 368.2 [M-H] - .

[0427] Preparation of intermediate B4.(S)-2-((S)-2,2-dicyano-1-methoxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0428] Step 1: Under nitrogen protection, N-tert-butoxycarbonyl-L-proline (5.0 g, 23.23 mmol) was dissolved in dichloromethane (50 mL), and EDCI was added sequentially. . HCl (5.3 g, 27.87 mmol), HOBT (3.8 g, 27.87 mmol), and triethylamine (4.7 g, 46.46 mmol) were added. The mixture was stirred at room temperature for 0.5 h. Malononitrile (1.5 g, 23.23 mmol) was then added, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as eluent to obtain (S)-2-((S)-2,2-dicyano-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (yellow oil, 5.7 g, 93.2%). MS (ESI) + m / z = 262.1 [MH] - .

[0429] Step 2: Under nitrogen protection, (S)-2-((S)-2,2-dicyano-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.39 mmol) was dissolved in THF (30 mL), cooled to -78 °C, and a THF solution of trimethylsilyldiazomethane (2 M, 2.9 mL, 5.70 mmol) was slowly added dropwise. The mixture was then brought back to room temperature and stirred for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 1) as eluent to obtain (S)-2-((S)-2,2-dicyano-1-methoxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (yellow oil, 1.3 g, 41.1%). MS (ESI) + m / z = 276.1 [MH] - .

[0430] Preparation of intermediate B5-B7

[0431] Intermediates B5-B7 were prepared using commercially available or prepared acid compounds as raw materials, following the method for synthesizing intermediate B4. See Table 3.

[0432] Table 3. Structure, characterization data and starting materials of intermediates B5-B7

[0433] Preparation of intermediate B8, 2-(dimethoxymethylene)malononitrile

[0434] Dissolve ethylene-1,1,2,2-tetracarbonitrile (5.0 g, 39.0 mmol) in methanol (15 mL), add urea (703.0 mg, 11.7 mmol), stir at room temperature for 1 h, after the reaction is complete, slowly add MTBE (20 mL), cool to -65 °C, stir to precipitate a large amount of solid, filter, dry the filter cake to obtain 2-(dimethoxymethylene)propanedinitrile (off-white solid, 2.5 g, 46.3%). MS (ESI + )m / z = 139.2 [M+H] + .

[0435] Preparation of intermediate B9, (R)-tert-butyl 3-(2,2-dicyano-1-methoxyvinyl)piperidine-1-carboxylate

[0436] Intermediate B9 is prepared according to the procedure for synthesizing intermediate B2, using (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as the starting material.

[0437] Preparation of the fourth group of preparation examples intermediates C1-C20

[0438] Preparation of intermediate C1, 7-(4-iodo-2-methylphenoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-d

[0439] First step: dissolve 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (7.0 g, 32.86 mmol) in concentrated hydrochloric acid (70 mL), add copper chloride dihydrate (1.4 g, 8.54 mmol), cool to 0 °C, slowly add a solution of sodium nitrite (2.3 g, 32.86 mmol) in water (12 mL). Stir overnight after returning to room temperature. After the reaction is complete, add water (50 mL) to the reaction solution, precipitate a solid, filter, dry the filter cake to obtain 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (pale yellow solid, 6 g). MS (ESI + )m / z = 231.9 [M+H] + .

[0440] Second step: 7-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (6.0 g, 25.81 mmol) was dissolved in 1,4-dioxane (60 mL) under nitrogen protection, and Pd(dppf)Cl2.CH2Cl2(1.1 g, 1.29 mmol), bis(pinacolato)diboron (9.8 g, 38.71 mmol) and potassium acetate (7.6 g, 77.43 mmol) were added successively. The reaction was heated to 100 °C and stirred for 4 h. After the reaction was completed, the reaction was cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 5) as eluent to obtain 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 4.8 g, 52.3% for two steps). MS (ESI + )m / z = 198.1 [M-82+H] + .

[0441] Third step: 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.3 g, 7.8 mmol) was dissolved in ethanol (20 mL), and aqueous NaOH solution (1 M, 7.8 mL, 7.8 mmol) was added. The reaction was cooled to 0 °C, and aqueous H2O2 solution (1 M, 7.8 mL, 7.8 mmol) was slowly added dropwise. The reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was restored to room temperature, and aqueous HCl solution (1 M) was added to the reaction solution to adjust the pH to 2. The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 20) as eluent to obtain 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (yellow solid, 0.7 g, 88.8%). MS (ESI + )m / z = 170.1 [M+H] + .

[0442] Fourth step: 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-ol (2.5 g, 14.74 mmol) was dissolved in methanol (30 mL) under nitrogen protection, and Pd / C (1.57 g, 14.74 mmol) was added, and deuterium was replaced. The reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain [1,2,4]triazolo[1,5-a]pyridin-2-deuterium-7-ol (yellow solid, 1.8 g, 89.7%). MS (ESI+ m / z = 137.2 [M+H] + .

[0443] Step 5: [1,2,4]Triazolo[1,5-a]pyridin-2-de-7-ol (2.5 g, 18.36 mmol) was dissolved in DMF (30 mL), cooled to 0 °C, and then Cs2CO3 (12.0 g, 36.73 mmol) and 2-fluoro-5-nitrotoluene (2.9 g, 18.36 mmol) were added successively. The reaction was stirred at 50 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, and water (100 mL) was added to the reaction. A solid was precipitated, which was filtered and dried to give 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-de (yellow solid, 3.5 g, 70.3 %). MS (ESI + m / z = 272.1 [M+H] + .

[0444] Step 6: 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-de (3.3 g, 12.17 mmol) was dissolved in a mixture of ethanol and water (2 / 1 v / v, 51 mL), and then iron powder (1.4 g, 24.34 mmol) and ammonium chloride (2.6 g, 48.66 mmol) were added successively. The reaction was stirred at 100 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, and the reaction was filtered with celite. The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-deoxy)oxy)-3-methylaniline (yellow solid, 2.5 g, 85.2 %). MS (ESI + m / z = 242.2 [M+H] + .

[0445] Step 7: 4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-deuterium)oxy)-3- methyl aniline (2.8 g, 11.61 mmol) was dissolved in acetonitrile (30 mL), p-toluenesulfonic acid (6.0 g, 34.82 mmol) was added, and the mixture was stirred at 0 °C for 10 min. A solution of potassium iodide (5.8 g, 34.82 mmol) and sodium nitrite (1.6 g, 23.21 mmol) in water (15 mL) was added dropwise. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 20) as the eluent to obtain 7-(4-iodo-2-methylphenoxy)-[l,2,4]triazolo[l,5-a]pyridin-2-deuterium (yellow solid, 3.3 g, 80.7%). MS (ESI + m / z = 353.0 [M+H] + .

[0446] Preparation of intermediate C2. 7-(2-chloro-4-iodophenoxy)-[l,2,4]triazolo[l,5-a]pyridine

[0447] Step 1: [l,2,4]Triazolo[l,5-a]pyridin-7-ol (25.0 g, 0.19 mol) was dissolved in acetonitrile (500 mL), K2CO3 (51.1 g, 0.37 mol) and 2-chloro-l-fluoro-4-nitrobenzene (39.0 g, 0.22 mol) were added in turn. The mixture was stirred at reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 10) as the eluent to obtain 7-(2-chloro-4-nitrophenoxy)-[l,2,4]triazolo[l,5-a]pyridine (yellow solid, 53 g, 98.6%). MS (ESI + m / z = 291.0 [M+H] + .

[0448] Second step: 7-(2-chloro-4-nitrophenoxy)-[l,2,4]triazolo[l,5-a]pyridine (45.0 g, 0.15 mol) was dissolved in anhydrous methanol (450 mL) under nitrogen protection, and Pd / C (4.5 g, 10% m / m) was added. Hydrogen was replaced, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered with diatomite, and the filtrate was concentrated under reduced pressure. The obtained residue was slurried with ethyl acetate / petroleum ether (1 / 1) to obtain 4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl)oxy)-3-chloroaniline (yellow solid, 30 g, 74.3%). MS (ESI + m / z = 261.0 [M+H] + .

[0449] Third step: 4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl)oxy)-3-chloroaniline (15.0 g, 57.54 mmol) was dissolved in acetonitrile (150 mL), and p-toluenesulfonic acid (29.7 g, 0.17 mol) was added. The temperature was lowered to 0°C, and the mixture was stirred for 10 min. An aqueous solution (75 mL) of potassium iodide (28.6 g, 0.17 mol) and sodium nitrite (7.9 g, 0.12 mol) was slowly added dropwise. The temperature was raised to room temperature, and the mixture was stirred overnight. After the reaction was completed, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 20) as the eluent to obtain 7-(2-chloro-4-iodophenoxy)-[l,2,4]triazolo[l,5-a]pyridine (yellow solid, 16 g, 74.8%). MS (ESI + m / z = 371.9 [M+H] + .

[0450] Preparation of intermediates C3-C17.

[0451] Intermediates C3-C8, C10-C17 were prepared according to the method for preparing intermediate C2, using commercially available hydroxy heteroaryl compounds and fluoronitrobenzene compounds as raw materials. As shown in Table 4. The first step of the substitution reaction can also be carried out under the following conditions: K2CO3, DMF, r.t.~60°C; or Cs2CO3, DMSO, 150°C; or Cs2CO3, NMP, 150°C; or Cs2CO3, DMF, r.t.

[0452] Table 4. Structures, characterization data and starting materials of intermediates C3-C8, C10-C17

[0453] Preparation of intermediate C9. 6-(2-chloro-4-iodophenoxy)-[1,2,4]triazolo[1,5- a]pyridine

[0454] First step: 6-aminopyridin-3-ol (5.0 g, 45.41 mmol) was dissolved in DMF (50 mL), 2-chloro-1-fluoro-4-nitrobenzene (9.6 g, 54.49 mmol) and Cs2CO3(44.4 g, 0.14 mol) were added successively, stirred at room temperature overnight. After the reaction was completed, water (150 mL) was added to the reaction solution, and a solid was precipitated. The solid was filtered and dried to obtain 5-(2-chloro-4-nitrophenoxy)pyridin-2-amine (yellow solid, 9.7 g, 80.8%). MS (ESI + )m / z = 266.1 [M+H] + .

[0455] Second step: 5-(2-chloro-4-nitrophenoxy)pyridin-2-amine (9.0 g, 33.88 mmol) was dissolved in ethanol (90 mL), DMF-DMA (8.1 g, 67.76 mmol) was added, and the temperature was raised to reflux and stirred for 4 h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain N'-(5-(2-chloro-4-nitrophenoxy)pyridin-2-yl)-N,N-dimethylformamidine (pale yellow solid, 9 g, crude). MS (ESI + )m / z = 321.1 [M+H] + .

[0456] Third step: N'-(5-(2-chloro-4-nitrophenoxy)pyridin-2-yl)-N,N-dimethylformamidine (9.0 g, 28.06 mmol) was dissolved in methanol (100 mL), pyridine (2.4 g, 30.87 mmol) and hydroxylamine sulfonic acid (7.9 g, 70.15 mmol) were added successively, and the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 6-(2-chloro-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid, 8.0 g, two-step yield: 81.2%). MS (ESI + )m / z = 291.0 [M+H] + .

[0457] Fourth step, fifth step: 6-(2-chloro-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine was used as a raw material, and 6-(2-chloro-4-iodophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (yellow solid) was prepared according to the method of the sixth step and the seventh step of the synthesis of intermediate C1. MS (ESI + )m / z = 371.9 [M+H]+ .

[0458] Preparation of intermediate C18. 6-(4-bromo-2-chlorooxy)-[1,2,4]triazolo[1,5- a]pyridine

[0459] First step: under nitrogen protection, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.08 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydroxide aqueous solution (2 M, 6.2 mL, 12.24 mmol) and hydrogen peroxide (30%, 1.3 mL, 12.24 mmol) were added in turn at 0 °C, slowly warmed to room temperature and stirred for 3 h, after the reaction was completed, the pH was adjusted to 3-4 with hydrochloric acid (2 M), the mixture was extracted with dichloromethane / methanol (5 / 1) (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (10%) as eluent to obtain [1,2,4]triazolo[1,5-a]pyridin-6-ol (white solid, 260 mg, 47.2%). MS (ESI + )m / z = 136.1 [M+H] + .

[0460] Second step: under nitrogen protection, [1,2,4]triazolo[1,5-a]pyridin-6-ol (400.0 mg, 2.96 mmol) was dissolved in DMF (10 mL), K2CO3 (1.2 g, 8.88 mmol) and 4-bromo-2-chloro-1-fluorobenzene (620.0 mg, 2.96 mmol) were added in turn, warmed to 100 °C and stirred for 3 h, after the reaction was completed, water (10 mL) was added, extracted with dichloromethane / methanol (10 / 1) (15 mL x 3), the combined organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (10%) as eluent to obtain 6-(4-bromo-2-chlorooxy)-[1,2,4]triazolo[1,5-a]pyridine (brown oil, 290 mg, 30.2%). MS (ESI + )m / z = 323.8 [M+H] + .

[0461] Preparation of intermediate C19. 7-(4-bromo-2-chlorophenoxy)-[1,2,4]triazolo[1,5- a]pyridin-2-d

[0462] First Step, Second Step: 4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-d)oxy)-3- chloroaniline (pale yellow solid) was prepared from [l,2,4]triazolo[l,5-a]pyridin-2-d-7-ol-d and 2-chloro-l-fluoro-4-nitrobenzene according to the method of the fifth step and the sixth step of the synthesis of intermediate CI. MS (ESI + m / z = 263.1 [M+H] + .

[0463] Third Step: 4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-d)oxy)-3-chloroaniline (660.0 mg, 2.52 mmol) was dissolved in acetonitrile (8 mL) under nitrogen protection, cuprous bromide (434.1 mg, 3.03 mmol) was added, the temperature was lowered to 0 °C, and tert-butyl nitrite (520.2 mg, 5.04 mmol) was slowly added, and the temperature was raised to 80 °C and stirred for 1 h. After the reaction was completed, the temperature was lowered to room temperature, water (10 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient to give 7-(4-bromo-2-chlorophenoxy)-[l,2,4]triazolo[l,5-a]pyridin-2-d (brown solid, 550 mg, 67.0%). MS (ESI + m / z = 326.9 [M+H] + .

[0464] Preparation of Intermediate C20. 5-(4-bromo-2-chloro-6-fluorophenoxy)-l-methyl-lH- benzo[d]imidazole

[0465] 3-chloro-5-fluoro-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)aniline (yellow solid, 960 mg, 96.2%) was prepared from l-chloro-2,3-difluoro-5-nitrobenzene and l-methyl-lH- benzo[d]imidazol-5-ol according to the method of the synthesis of intermediate CI9. MS (ESI + m / z = 356.9 [M+H] + .

[0466] Preparation of Intermediate D1-D7

[0467] Preparation of Intermediate D1. 7-(4-hydrazinyl-2-methylphenoxy)-[l,2,4]triazolo[l,5- a]pyridin-2-d

[0468] Step 1: Intermediate C1 (2.0 g, 5.68 mmol) was dissolved in DMF (20 mL), and then Cs2CO3 (2.8 g, 8.52 mmol), cuprous iodide (108.2 mg, 0.57 mmol), 1,10-phenanthroline (112.6 mg, 0.57 mmol) and tert-butyl hydrazinecarboxylate (900.7 mg, 6.82 mmol) were added successively. The reaction was stirred at 100 °C for 2 h. After the reaction was completed, the reaction was cooled to room temperature, water (60 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate as the eluent to obtain tert-butyl 2-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-d)oxy)-3-methylphenyl)hydrazine-1-carboxylate (yellow solid, 1.8 g, 88.9%). MS (ESI + m / z = 357.1 [M+H] + .

[0469] Step 2: tert-Butyl 2-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-d)oxy)-3-methylphenyl)hydrazine-1-carboxylate (1.8 g, 5.05 mmol) was dissolved in a hydrochloric acid solution in dioxane (4 M, 20 mL). It was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain 7-(4-hydrazinyl-2-methylphenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-d (yellow solid, 1.2 g). MS (ESI + m / z = 257.2 [M+H] + .

[0470] Preparation of intermediates D2-D7

[0471] Intermediates D2-D7 were prepared using the preparation method of intermediate D1 described above, using intermediates C2-C5, C7-C8 as raw materials. As shown in Table 5.

[0472] Table 5. Structures of intermediates D2-D7, raw materials of intermediates and characterization data

[0473] Preparation of intermediates E1-E19

[0474] Intermediate E1. 2-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)morpholine-4-carbaldehyde

[0475] Step 1: Intermediate B1 (1.0 g, 3.41 mmol) was dissolved in anhydrous ethanol (10 mL) under nitrogen protection, and then intermediate D2 (914.8 mg, 3.41 mmol) and TEA (1.0 g, 10.23 mmol) were added successively. Stirring at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 1) as the eluent to obtain 2-(5-amino-4-cyano-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazol-3-yl)morpholine-4-carboxylic acid tert-butyl ester (yellow solid, 350 mg, 19.4%). MS (ESI + )m / z = 530.2 [M+H] + .

[0476] Step 2: 2-(5-amino-4-cyano-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazol-3-yl)morpholine-4-carboxylic acid tert-butyl ester (200.0 mg, 0.38 mmol) was dissolved in formamide (2 mL). Stirring at 180°C for 2 h. After the reaction was completed, it was cooled to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (E)-2-(4-((aminomethylene)amino)-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)morpholine-4-carboxylic acid tert-butyl ester (brown oil, 250 mg, crude). MS (ESI + )m / z = 485.2 [M+H] + .

[0477] Preparation of intermediates E2-E18

[0478] Intermediates E2-E18 were prepared according to the method for synthesizing intermediate E1 using intermediates B1-B9 and intermediates D1-D7 as raw materials. As shown in Table 6.

[0479] Table 6. Structures of intermediates E2-E18, intermediate raw materials, and characterization data

[0480] Preparation of intermediate E19. 1-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3-methoxy-4-methyl-1H-pyrazolo[3,4-d]pyrimidine

[0481] First Step: 7-(2-chloro-4-hydrazinylphenoxy)-[l,2,4]triazolo[l,5-a]pyridine (Intermediate D4, 3.0 g, 10.88 mmol) was dissolved in absolute ethanol (30 mL) under nitrogen protection, 2-(dimethoxymethyl)propanedinitrile (Intermediate B8, 1.5 g, 10.88 mmol) and triethylamine (2.2 g, 21.76 mmol) were added successively, and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, slurried with ethanol (20 mL), and filtered under suction. The filter cake was dried to give 1-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-5-amino-3-methoxy-lH- pyrazole-4-carbonitrile (white solid, 3 g, crude).

[0482] Second Step: 1-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-5-amino-3-methoxy- lH-pyrazole-4-carbonitrile (3.0 g, 7.86 mmol) was dissolved in formic acid (30 mL), and stirred at reflux overnight. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to give 1-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3-methoxy-l,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one (yellow oil, 2.8 g, crude). MS (ESI + m / z = 410.0 [M+H] + .

[0483] Third Step: 1-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3-methoxy-l,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one (2.8 g, 6.85 mmol) was dissolved in 1,4-dioxane (5 mL) under nitrogen protection, and phosphorus oxychloride (10.5 g, 68.46 mmol) was added. The reaction solution was stirred at reflux for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated by silica gel column chromatography using methanol / dichloromethane (10%) as the eluent to give 1-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-chloro-3-methoxy-lH- pyrazolo[3,4-d]pyrimidine (yellow solid, 1.2 g, 25.8% yield over three steps). MS (ESI + m / z = 429.0 [M+H] + .

[0484] Fourth step: 1-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-chloro-3- methoxy-1H-pyrazolo[3,4-d]pyrimidine (4.5 g, 10.51 mmol) was dissolved in 1,4-dioxane and water mixture (10 / 1 v / v, 55 mL) under nitrogen protection, Pd(dppf)Cl2CH2Cl2(858.1 mg, 1.05 mmol), K2CO3(5.8 g, 42.03 mmol) and trimethylboroxine (13.2 g, 0.11 mol) were added successively, and the mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (10%) as the eluent to obtain 1-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3-methoxy-4-methyl-1H- pyrazolo[3,4-d]pyrimidine (yellow solid, 1.2 g, 28.0%). MS (ESI + m / z = 408.0 [M+H] + .

[0485] Seventh group of preparation examples: preparation of intermediates F1-F10

[0486] Preparation of intermediate F1. 6-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)- [1,2,4]triazolo[1,5-a]pyridine

[0487] 6-(4-bromo-2-chlorooxy)-[1,2,4]triazolo[1,5-a]pyridine (intermediate C18, 260 mg, 0.80 mmol) was dissolved in 1,4-dioxane (5 mL) under nitrogen protection, potassium acetate (235.9 mg, 2.40 mmol), Pd(dppf)Cl2CH2Cl2(58.6 mg, 0.08 mmol) and pinacol diboronic acid (244.1 mg, 0.96 mmol) were added successively, and the mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 10) as the eluent to obtain 6-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (brown oil, 240 mg, 80.6%). MS (ESI + m / z = 372.1 [M+H] + .

[0488] Intermediates F2-F7. Preparation of intermediates F2-F7

[0489] Intermediates F2-F7 were prepared using the preparation method of intermediate Fl, intermediates C11-C12, C15-C17, C19 and commercially available compounds as starting materials, see Table 7.

[0490] Table 7. Structures of intermediates F2-F7, starting materials of intermediates and characterization data

[0491] Intermediate F8. Preparation of 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine

[0492] Under nitrogen protection, 7-(2-fluoro-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (intermediate C10, 500.0 mg, 1.82 mmol) was dissolved in acetonitrile (40 mL), pinacol diboronic acid (2.3 g, 9.12 mmol) and tetrabutylammonium hydrogen sulfate (619.1 mg, 1.82 mmol) were added in turn, and a carbon rod electrode was inserted as anode and cathode respectively. The temperature was lowered to 0 °C, and pyridine (187.5 mg, 2.37 mmol) and tert-butyl nitrite (564.1 mg, 5.47 mmol) were added, the voltage was set to 15 V, the current was 16 mA, and the reaction was stirred at room temperature for 18 h. After the reaction was completed, saturated brine solution (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as eluent gradient to obtain 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 600 mg, 92.6%). MS (ESI + )m / z = 356.1 [M+H] + .

[0493] Intermediate F9. Preparation of 7-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine

[0494] Under nitrogen protection, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloroaniline (2.0 g, 7.67 mmol) was dissolved in acetonitrile (20 mL), and pinacol diboronate (3.9 g, 15.34 mmol) and tert-butyl nitrite (2.4 g, 23.02 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 4 h. After the reaction was complete and cooled to room temperature, water (10 mL) was added to the reaction solution. 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. The residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (20%) as the eluent to obtain 7-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 2 g, 70.1%). MS (ESI) + m / z = 372.1 [M+H] + .

[0495] Preparation of intermediate F10. 7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine

[0496] Using 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (2.0 g, 8.32 mmol) as a starting material, 7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (yellow oil, 1.7 g, 58.2%) was prepared according to the method for synthesizing intermediate F9. MS (ESI) + m / z = 352.2[M+H] + .

[0497] Preparation of the final product in Group 8

[0498] Example 1. Preparation of 1-(3-(4-amino-7-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (final product 1)

[0499] First Step: Intermediate Al (300.0 mg, 0.81 mmol) was dissolved in DMF (5 mL) under nitrogen protection, and then CuI (154.2 mg, 0.81 mmol), (1S,2S)-1,2-cyclohexanediamine (184.9 mg, 1.62 mmol), potassium phosphate (343.8 mg, 1.62 mmol) and 5-(4-iodo-2-methylphenoxy)-1-methyl-1H-benzo[d]imidazole (Intermediate C4, 354.2 mg, 0.97 mmol) were added successively. The reaction mixture was stirred at 110 °C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 2-1 / 0) as eluent gradient to give tert-butyl 5-(4-(((dimethylamino)methylene)amino)-7-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)- carboxylate (brown solid, 220 mg, 44.7%). MS (ESI) m / z = 607.2 [M+H] + MS (ESI) m / z = 607.2 [M+H] + .

[0500] Second Step: tert-Butyl 5-(4-(((dimethylamino)methylene)amino)-7-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)- carboxylate (230.0 mg, 0.38 mmol) was dissolved in ethanol (3 mL), and ethylenediamine (91.1 mg, 1.52 mmol) was added. The reaction mixture was stirred at reflux overnight. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with methanol / dichloromethane (1 / 20) as eluent to give tert-butyl 5-(4-amino-7-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (brown solid, 120 mg, 57.1%).

[0501] Step 3: tert-Butyl 5-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (120.0 mg, 0.22 mmol) was dissolved in MeOH (2 mL) under nitrogen and Pd / C (120 mg, 100% m / m) was added. The hydrogen was replaced and the reaction was stirred at 65 °C overnight. After the reaction was complete, the reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (pale yellow solid, 100 mg, 83.1%). MS (ESI) m / z = 554.2 [M+H] + m / z = 554.2 [M+H] + .

[0502] Step 4: tert-Butyl 3-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (100.0 mg, 0.18 mmol) was dissolved in DCM (1 mL) and a solution of hydrochloric acid in 1,4-dioxane (4 M, 0.45 mL, 1.81 mmol) was added. The reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was concentrated under reduced pressure to give 7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (white solid, 80 mg, 89.9%). MS (ESI) m / z = 454.1 [M+H] + m / z = 554.2 [M+H] + .

[0503] Step 5: 7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-5-(piperidin-3- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (80.0 mg, 0.16 mmol) was dissolved in THF (1 mL), saturated aqueous sodium bicarbonate (0.5 mL) was added, and the solution was cooled to 0 °C. Acryloyl chloride (13.3 mg, 0.15 mmol) was added. The reaction was stirred at 0 °C for 1 h. After the reaction was complete, the solution was allowed to warm to room temperature, water (1 mL) was added, and the mixture was extracted with ethyl acetate (3 mL). The combined organic layers were washed with saturated brine (1 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give l-(3-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l-yl)prop-2-en-l-one.

[0504] White solid, MS (ESI + m / z = 508.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.10 (s, 1H), 7.73-7.67 (m, 1H), 7.60-7.64 (m, 2H), 7.40-7.36 (m, 1H), 7.17-7.15 (m, 1H), 7.06-7.00 (m, 1H), 6.99-6.70 (m, 4H), 6.26-6.05 (m, 1H), 5.80-5.58 (m, 1H), 4.67-4.45 (m, 1H), 4.29-4.12 (m, 1H), 3.85 (s, 3H), 3.23-2.98 (m, 2H), 2.76-2.57 (m, 1H), 2.31 (s, 3H), 2.21-2.10 (m, 1H), 1.87-1.79 (m, 1H), 1.71-1.55 (m, 2H).

[0505] Example 2. Preparation of l-(5-(4-amino-7-(3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6- dihydropyridin-l(2H)-yl)prop-2-en-l-one (final product 4)

[0506] Step 1: Into a 20 mL reaction vial was placed tert-butyl 5-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (70 mg, 0.10 mmol), trifluoroacetic acid (6.3 mL) and water (0.7 mL), warmed to 60 °C with stirring for 16 h, concentrated under reduced pressure, the resulting crude was used directly in the next step without purification. MS (ESI + m / z = 452.3 [M+H] + .

[0507] Step 2: Into a 20 mL reaction vial was placed tert-butyl 5-(4-amino-7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (70 mg, 0.10 mmol), trifluoroacetic acid (6.3 mL) and water (0.7 mL), warmed to 60 °C with stirring for 16 h, concentrated under reduced pressure, the resulting crude was used directly in the next step without purification. MS (ESI

[0508] White solid, MS (ESI + m / z = 452.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.99 (d, J = 13.0 Hz, 1H), 8.36 (s, 1H), 8.09 - 7.46 (m, 6H), 7.26 (s, 2H), 7.16 - 6.87 (m, 2H), 6.21 - 6.16 (m, 1H), 5.99 (d, J = 18.4 Hz, 1H), 5.77 - 5.70 (m, 1H), 4.44 (s, 1H), 4.38 (s, 1H), 3.98 (s, 3H), 3.80 - 3.74 (m, 2H), 2.36 (s, 1H), 2.31 (s, 4H).

[0509] Example 3. Preparation of 1-(3-(7-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-deuterio)oxy)-3- methylphenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (final product 6)

[0510] First step: Intermediate A2 (190.0 mg, 0.54 mmol) was dissolved in DMF (5 mL) under nitrogen protection, and CuI (102.8 mg, 0.54 mmol), (1S,2S)-1,2-cyclohexanediamine (123.2 mg, 1.08 mmol), K3PO4 (233.4 mg, 1.08 mmol) and Intermediate CI (221 mg, 0.59 mmol) were added successively. The reaction was stirred at 100 °C for 2 h. After the reaction was completed, the reaction was cooled to room temperature, water (15 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with methanol / methylene chloride (1 / 20) as the eluent to obtain tert-butyl 3-(7-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-deuterio)oxy)-3-methylphenyl)-4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (yellow solid, 280 mg, 88.5%). MS (ESI) m / z = 597.3 [M+H] + m / z = 542.3 [M+H] + .

[0511] Second step: tert-Butyl 3-(7-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-deuterio)oxy)-3-methylphenyl)-4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (300.0 mg, 0.50 mmol) was dissolved in 1,4-dioxane (3 mL) in an autoclave, and ammonia (3 mmol) was added. The reaction was stirred at 90 °C overnight. After the reaction was completed, the reaction was cooled to room temperature, and the reaction was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(7-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yl-2-deuterio)oxy)-3-methylphenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (pale yellow solid, 250 mg). MS (ESI) m / z = 542.3 [M+H] + m / z = 542.3 [M+H] + .

[0512] Step 3: Dissolve 3-(7-(4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-deuterium)oxy)-3- methylphenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l -yl tert-butylcarbamate (250.0 mg, 0.46 mmol) in DCM (2 mL), add TFA (2 mL). Stir at room temperature for 1 h. After the reaction is complete, concentrate the reaction under reduced pressure to give 7-(4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-deuterium)oxy)-3-methylphenyl)-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yellow oil, 200 mg).

[0513] Step 4: Dissolve 7-(4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-deuterium)oxy)-3-methylphenyl)-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200.0 mg, 0.45 mmol) in THF (2 mL), add saturated sodium bicarbonate solution (2 mL), cool to 0 °C, slowly add acryloyl chloride in THF (8.2 mg, 0.09 mmol, 2 mL). Stir at 0 °C for 0.5 h. After the reaction is complete, restore to room temperature, add water (5 mL) to the reaction, extract the mixture with ethyl acetate (5 mL x 3), dry the combined organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, separate the residue obtained by silica gel thin layer chromatography plate with methanol / dichloromethane (1 / 10) as developing agent to give l-(3-(7-(4-(([l,2,4]triazolo[l,5-a]pyridin-7-yl-2-deuterium)oxy)-3-methylphenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l-yl)prop-2-en-l-one.

[0514] White solid, MS (ESI + m / z = 496.3 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.97 - 8.36 (m, 1H), 8.14 (s, 1H), 7.90 - 7.74 (m, 2H), 7.48 (d, J = 10.2 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.11 - 6.74 (m, 5H), 6.30 - 6.04 (m, 1H), 5.81 - 5.61 (m, 1H), 4.59 - 4.38 (m, 1H), 4.32 - 4.18 (m, 1H), 3.24 - 2.96 (m, 2H), 2.67 (t, J = 11.9 Hz, 1H), 2.24 (s, 3H), 2.21 - 2.11 (m, 1H), 1.91 - 1.49 (m, 3H).

[0515] Example 4. Preparation of 1-(3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (Final Product 9, Final Product 10, Final Product 11)

[0516] First Step: tert-Butyl 5-(4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate Al, 12.0 g, 32.39 mmol) was dissolved in DMF (120 mL) under nitrogen protection, and CuI (6.2 g, 32.39 mmol), K3PO4 (13.8 g, 64.78 mmol) and 7-(2-chloro-4-iodophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (Intermediate C2, 14.4 g, 38.87 mmol) were added in turn. The temperature was raised to 100 °C and stirred for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / methylene chloride (50%) as eluent to give tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yellow solid, 6 g, 30.2%). MS (ESI + m / z = 614.1 [M+H] + .

[0517] Second step: in a high-pressure reaction kettle, 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-(((dimethylamino)methylene)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.0 g, 4.89 mmol) was dissolved in 1,4-dioxane (30 mL), and ammonia water (30 mL) was added. The temperature was raised to 90°C and stirred overnight. After the reaction was completed, it was cooled to room temperature, and the reaction liquid was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (pale yellow solid, 1.8 g, crude). MS (ESI + )m / z = 559.2 [M+H] + .

[0518] Third step: with 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.8 g, 3.22 mmol) as the raw material, 3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (pale yellow solid, 1.5 g, crude) was prepared according to the method of the third step of the synthesis of the final product 1. MS (ESI + )m / z = 561.2 [M+H] + .

[0519] Fourth step: 3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.67 mmol) was dissolved in DCM (20 mL), and TFA (15 mL) was added. Stirring at room temperature for 2 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to give 7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (yellow oil, 1.5 g, crude). MS (ESI + )m / z = 461.1 [M+H] + .

[0520] Step 5: 7-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-5-(piperidin-3- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.5 g, 3.25 mmol) was dissolved in THF (20 mL), and saturated sodium bicarbonate solution (20 mL) was added. The solution was cooled to 0 °C, and acryloyl chloride in THF (2 mL, 147.3 mg, 1.63 mmol) was added slowly. The solution was stirred at 0 °C for 0.5 h. After the reaction was complete, the solution was allowed to warm to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (10%) as the eluent to give l-(3-(7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l-yl)prop-2-en-l-one. MS (ESI) m / z = 515.1 [M+H] + m / z = 515.1 [M+H] + .

[0521] Step 6: l-(3-(7-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-amino-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l-yl)prop-2-en-l-one was separated by supercritical fluid chromatography chiral resolution (column type: OD-H 4.6 mm x 250 mm, 3 μm; mobile phase A: CO2, B: MeOH; gradient: 40% to 40% of B in 15 min; flow rate: 2 mL / min) to give two products, the specific configuration of which was not known.

[0522] First eluted product

[0523] White solid, MS (ESI) m / z = 515.1 [M+H] + m / z = 515.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 7.5 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J = 9.0, 2.7 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.10 (dd, J = 7.5, 2.7 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.98 - 6.79 (m, 2H), 6.29 - 5.99 (m, 1H), 5.82 - 5.56 (m, 1H), 4.71 - 4.42 (m, 1H), 4.34 - 4.03 (m, 1H), 3.22 - 2.99 (m, 2H), 2.67 (t, J = 13.1 Hz, 1H), 2.27 - 2.07 (m, 1H), 1.88 - 1.56 (m, 3H).

[0524] Second eluting product

[0525] Yellow solid, MS (ESI + )m / z = 515.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 7.5 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J = 9.0, 2.7 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.10 (dd, J = 7.5, 2.7 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.98 - 6.79 (m, 2H), 6.29 - 5.99 (m, 1H), 5.82 - 5.56 (m, 1H), 4.71 - 4.42 (m, 1H), 4.34 - 4.03 (m, 1H), 3.22 - 2.99 (m, 2H), 2.67 (t, J = 13.1 Hz, 1H), 2.27 - 2.07 (m, 1H), 1.88 - 1.56 (m, 3H).

[0526] Example 5. 1-(3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-chlorophenyl)-4- amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (Final Product 12)

[0527] Final Product 12 was prepared from Intermediate A2 and Intermediate C9 following the procedure for the synthesis of Final Product 6.

[0528] MS (ESI +m / z = 515.1 [M+H] + . 1 H NMR (300 MHz, CDC13) δ 8.35 (s, 1H), 8.32-8.28 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.65 (dd, J = 8.7, 2.4 Hz, 1H), 7.50-7.42 (m, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.69-6.57 (m, 1H), 6.48-6.39 (m, 1H), 5.84-5.79 (m, 1H), 4.69 (d, J = 13.5 Hz, 1H), 4.11 (d, J = 13.5 Hz, 1H), 3.26 (t, J = 12.3 Hz, 1H), 3.07 (t, J = 11.1 Hz, 1H), 2.60-2.44 (m, 1H), 2.31 (d, J = 12.6 Hz, 1H), 2.09-1.87 (m, 2H), 1.77-1.56 (m, 1H).

[0529] Example 6. Preparation of l-(3-(4-methyl-7-(3-methyl-4-((l-methyl-lH- benzimidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-l-yl)prop-2- en-l-one (Final Product 15)

[0530] Final Product 15 was prepared from Intermediate A4 and Intermediate C4 following the procedures for the first, third, fourth and fifth steps of the synthesis of Final Product 1.

[0531] White solid, MS (ESI + m / z = 507.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.20 (s, 1H), 7.85-7.72 (m, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.20 (s, 1H), 7.04 (dd, J = 8.7, 2.2 Hz, 1H), 6.99-6.80 (m, 2H), 6.14 (t, J = 14.9 Hz, 1H), 5.89-5.61 (m, 1H), 4.83-4.47 (m, 1H), 4.39-4.07 (m, 1H), 3.85 (s, 3H), 3.20-3.03 (m, 2H), 2.83 (d, J = 21.6 Hz, 3H), 2.72-2.58 (m, 1H), 2.34 (s, 3H), 2.22-2.10 (m, 1H), 1.93-1.76 (m, 2H), 1.70-1.41 (m, 1H).

[0532] Example 7. Preparation of l-(5-(4-methyl-7-(3-methyl-4-((l-methyl-lH- benzimidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin- 1(2H)-yl)prop-2-en-1-one (Final Product 16)

[0533] Final Product 16 was prepared from 4-methyl-5-(7-(3-methyl-4-((l-methyl-lH- benzimidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine- 1(2H)-carboxylic acid tert-butyl ester (intermediate product from the first step of the preparation of Final Product 15) following the procedure for the synthesis of Final Product 4.

[0534] White solid, MS (ESI + )m / z = 505.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.20 (s, 1H), 8.02 (s, 0.5H), 7.91 (s, 0.5H), 7.77 (s, 1H), 7.68-7.54 (m, 2H), 7.21 (s, 1H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 7.01-6.84 (m, 2H), 6.17 (d, J = 16.6 Hz, 1H), 6.09-5.98 (m, 1H), 5.81-5.65 (m, 1H), 4.38 (d, J = 16.5 Hz, 2H), 3.85 (s, 3H), 3.82-3.70 (m, 2H), 2.70 (s, 3H), 2.42-2.26 (m, 5H).

[0535] Example 8. Preparation of 1-(3-(7-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1- yl)prop-2-en-1-one (Final Product 17)

[0536] 1-(3-(7-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was prepared from Intermediate A3 and Intermediate C4 following the procedures for the first, third, fourth and fifth steps of the synthesis of Final Product 1.

[0537] White solid, MS (ESI + )m / z = 493.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.29 - 9.20 (m, 1H), 8.85 (s, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.68 - 7.59 (m, 2H), 7.20 (s, 1H), 7.08 - 7.02 (m, 1H), 6.97 - 6.83 (m, 2H), 6.20 - 6.08 (m, 1H), 5.76 - 5.61 (m, 1H), 4.71 - 4.41 (m, 1H), 4.30 - 4.08 (m, 1H), 3.85 (s, 3H), 3.29 - 2.71 (m, 3H), 2.34 (s, 3H), 2.22 - 2.15 (m, 1H), 1.97 - 1.75 (m, 2H), 1.65 - 1.46 (m, 1H).

[0538] Example 9. Preparation of 1-(5-(7-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6- dihydropyridin-1(2H)-yl)prop-2-en-1-one (Final Product 18)

[0539] Using tert-butyl 5-(7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (an intermediate obtained in the first step of preparing final product 17) as the starting material, l-(5-(7-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-l(2H)-yl)prop-2-en-l-one was prepared following the procedures of the fourth and fifth steps of synthesizing final product 1.

[0540] White solid, MS (ESI + m / z = 491.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.46 - 9.36 (m, 1H), 8.89 (s, 1H), 8.29 - 8.08 (m, 2H), 7.85 - 7.75 (m, 1H), 7.72 - 7.56 (m, 2H), 7.21 (s, 1H), 7.10 - 6.89 (m, 3H), 6.68 - 6.55 (m, 1H), 6.28 - 6.11 (m, 1H), 5.79 - 5.71 (m, 1H), 4.58 - 4.50 (m, 2H), 3.85 (s, 3H), 3.80 - 3.70 (m, 2H), 2.46 - 2.37 (m, 2H), 2.35 (s, 3H).

[0541] Example 10. Preparation of l-(2-(4-amino-l-(3-methyl-4-((l-methyl-lH- benzo[d]imidazol-5-yl)oxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-3-yl)morpholino)prop-2- en-l-one (final product 20)

[0542] First Step: 2-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)morpholine-4-carbaldehyde (Intermediate E1, 250.0 mg, 0.52 mmol) was dissolved in ethanol (3 mL), hydrochloric acid (6 M, 3 mL) was added. The reaction was stirred at reflux for 1 h. After the reaction was completed, it was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to adjust pH to 9, extracted with dichloromethane / methanol mixture (10 / 1, 5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3-(morpholin-2-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (pale yellow solid, 200 mg, 84.3%). MS (ESI + m / z = 457.1 [M+H] + .

[0543] Second Step: 1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3-(morpholin-2-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (200.0 mg, 0.44 mmol) was dissolved in THF (2 mL), saturated sodium bicarbonate solution (2 mL) was added, the temperature was lowered to 0 °C, and acryloyl chloride in THF (7.9 mg, 0.088 mmol, 1 mL) was added dropwise slowly. The temperature was raised to room temperature and stirred for 0.5 h. After the reaction was completed, water (5 mL) was added to the reaction, the mixture was extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 10) as eluent to give 1-(2-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)morpholinyl)prop-2-en-1-one

[0544] white solid, MS (ESI + m / z = 511.2 [M+H] + . 1H NMR (300 MHz, CDC13) δ 8.41 (s, 1H), 7.90 (s, 2H), 7.83-76 (m, 1H), 7.40-7.31 (m, 2H), 7.10-7.03 (m, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.86-6.68 (m, 1H), 6.44-6.36 (m, 1H), 5.86-5.77 (m, 1H), 5.08-4.92 (m, 1H), 4.41-3.89 (m, 3H), 3.91-3.74 (m, 5H), 3.53-3.31 (m, 1H), 2.40 (s, 3H).

[0545] Examples 11-20. Preparation of end products 19, 25, 27, 28, 30, 67, 81, 82, 137, 138

[0546] End products 19, 25, 27, 28, 30, 67, 81, 82, 137, 138 were prepared from intermediates E2-E5, E11, E13, E16-17 following the procedure for the synthesis of end product 20. See Table 8.

[0547] Table 8. Intermediate starting materials, structures, and characterization data required for the preparation of end products 19, 25, 27, 28, 30, 67, 81, 82, 137, 138

[0548] Example 21. 1-(5-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzimidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1-one (End product 21)

[0549] First Step: Dissolve 5-(4-amino-1-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- (methoxymethyl)piperidin-1-yl benzoate (Intermediate E9, 400.0 mg, 0.6 mmol) in DCM (5 mL), cool to 0 °C, add TMSI (600.0 mg, 3.0 mmol), stir at room temperature for 1 h, after the reaction is complete, add water (5 mL), extract the mixture with DCM (5 mL x 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 3-(6-(methoxymethyl)piperidin-3-yl)-1-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yellow solid, 200.0 mg, crude). MS (ESI + m / z = 499.2 [M+H] + .

[0550] Second Step: Use 3-(6-(methoxymethyl)piperidin-3-yl)-1-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the raw material, and prepare 1-(5-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzimidazol-5- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-(methoxymethyl)piperidin-1-yl)prop- 2-en-1-one according to the method for synthesizing the final product 20, second step.

[0551] White solid, MS (ESI + m / z = 553.3 [M+H] + . 1H NMR (300 MHz, CDC13) δ 8.43 (s, 1H), 8.02 - 7.79 (m, 3H), 7.40 - 7.31 (m, 2H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 6.97 (d, J = 10.2 Hz, 1H), 6.73 - 6.64 (m, 3H), 6.41 (dd, J = 16.8, 1.8 Hz, 1H), 5.82 (dd, J = 10.5, 1.5 Hz, 1H), 4.69 (d, J = 13.5 Hz, 1H), 4.43 - 4.29 (m, 1H), 3.87 (s, 3H), 3.86 - 3.79 (m, 1H), 3.66 - 3.56 (m, 1H), 3.43 (s, 3H), 3.22 - 3.11 (m, 1H), 2.93 - 2.79 (m, 1H), 2.45 - 2.36 (m, 4H), 2.31 - 2.20 (m, 1H), 2.06 (d, J = 13.8 Hz, 1H), 1.79 (brs, 1H).

[0552] 1-(5-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1-one by chiral resolution to give (R)-1-(5-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1- one and (S)-1-(5-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1-one (Final Product 83 and Final Product 84), both specifically in R or S configuration unknown.

[0553] Example 22. Preparation of 1-(4-((4-amino-1-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)piperidin-1-yl)prop-2- en-1-one (Final Product 34)

[0554] First Step: 3-methoxy-l-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate E6, 1.0 g, 2.49 mmol) was dissolved in DMF (10 mL) under nitrogen atmosphere, cooled to 0 °C and NaH (0.50 g, 12.46 mmol, 60%) was added slowly. The reaction mixture was stirred at 0 °C for 10 min. Then ethanethiol (0.77 g, 12.46 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was quenched with ice cold water (30 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as eluent to afford 4-amino-l-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-lH- pyrazolo[3,4-d]pyrimidin-3-ol (white solid, 800 mg, 82.9%). MS (ESI + )m / z = 388.1 [M+H] + .

[0555] Second Step: 4-amino-l-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5- yl)oxy)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-3-ol (200.0 mg, 0.52 mmol) was dissolved in DMSO (2 mL) and potassium carbonate (142.7 mg, 1.03 mmol) and l-Boc-4-chloropiperidine (567.1 mg, 2.58 mmol) were added sequentially. The reaction mixture was stirred at 150 °C for 0.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography using methanol / dichloromethane (1 / 10) as eluent to afford 4-((4-amino-l-(3-methyl-4-((l-methyl-lH-benzo[d]imidazol-5-yl)oxy)phenyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)oxy)piperidine-l-carboxylic acid tert-butyl ester (yellow solid, 40 mg, 13.6%). MS (ESI + )m / z = 571.3 [M+H] + .

[0556] Step 3, 4: tert-Butyl 4-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)piperidin-1-yl)pentan-2- one was prepared according to the procedures for the synthesis of the final product 6, step 3 and step 4, using tert-butyl 4-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)piperidin-1-yl)pentan-2-ol as the starting material.

[0557] White solid, MS (ESI + m / z = 525.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.37 (s, 1H), 8.00 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.8, 2.8 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.11 - 7.06 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.62 (dd, J = 16.8, 10.4 Hz, 1H), 6.31 (dd, J = 16.8, 1.6 Hz, 1H), 5.94 (br s, 1H), 5.78 - 5.70 (m, 1H), 5.32 - 5.23 (m, 1H), 4.22 - 4.08 (m, 1H), 3.88 (s, 4H), 3.59 - 3.42 (m, 2H), 2.37 (s, 3H), 2.17 - 2.04 (m, 2H), 2.03 - 1.86 (m, 2H).

[0558] Examples 23-31. Preparation of final products 36, 37, 40-41, 44-45, 85, 139, 147

[0559] Final products 36, 37, 40-41, 44-45, 85, 139, 147 were prepared according to the procedure for the synthesis of the final product 34, using intermediates E6-E8, E12, E18, E191 and the corresponding halogenated heterocyclyl compounds as starting materials, as shown in Table 9. The second substitution reaction conditions can also be: tert-butyl 4-bromopiperidine-1-carboxylate, K2CO3, DMF, 70 °C

[0560] Table 9. Intermediate starting materials, structures, and characterization data required for the preparation of final products 36, 37, 40-41, 44-45, 85, 139, 147

[0561] Example 32. 1-(3-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)azetidin-1-yl)prop-2-en-1-one (Final Product 38)

[0562] First Step: 4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-ol (130.0 mg, 0.34 mmol) was dissolved in DMSO (3.0 mL), potassium carbonate (94.0 mg, 0.68 mmol) and 3-chloroazetidine-1- carboxylate benzyl ester (384.0 mg, 1.7 mmol) were added successively, and stirred at 150 °C for 1 h. After cooling to room temperature, water (5.0 mL) was added, and the mixture was extracted with dichloromethane (5.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography using methanol / dichloromethane (1 / 10) as the developing agent to give 3-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)azetidine-1-carboxylate benzyl ester (yellow solid, 60.0 mg, 31.0 %). MS (ESI m / z = 577.1 [M+H] + m / z = 577.1 [M+H] + .

[0563] Second Step: 3-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy)azetidine-1-carboxylate benzyl ester (60.0 mg, 0.1 mmol) was dissolved in EtOH (1.0 mL), and aqueous KOH solution (2 M, 1.0 mL) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give 3-(azetidin-3-yloxy)-1-(3-methyl-4-((1-methyl-1H- benzoimidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (brown oil, 30.0 mg, crude).

[0564] Step 3: 1-(3-((4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)oxy)azetidin-1-yl)propan-2-en-1-one was prepared from 3-(azetidin-3-yloxy)-1-(3-methyl-4-((1-methyl-1H-benzoimidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine following the procedure for the synthesis of the final product 6, Step 4.

[0565] White solid, MS (ESI + m / z = 497.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 8.36 (s, 1H), 8.24 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.23 - 7.09 (m, 2H), 6.96 (d, J = 8.8 Hz, 1H), 6.40 (dd, J = 16.0, 10.2 Hz, 1H), 6.28 (dd, J = 16.0, 2.0 Hz, 1H), 5.77 (dd, J = 10.2, 2.0 Hz, 1H), 5.60 - 5.51 (m, 1H), 4.83 - 4.77 (m, 1H), 4.61 - 4.50 (m, 2H), 4.37 - 4.26 (m, 1H), 3.95 (s, 3H), 2.33 (s, 3H).

[0566] Example 33. Preparation of 1-(2-(4-amino-1-(3-methyl-4-((1-methyl-1H- benzoimidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyrrolidin-1-yl)but-2-yn-1- one (Final product 46)

[0567] Final product 46 was prepared from Intermediate E10 following the procedure for the synthesis of the final product 21.

[0568] White solid, MS (ESI + m / z = 507.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.35 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.83-7.75 (m, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 5.63 (d, J = 6.9 Hz, 1H), 4.04-3.90 (m, 1H), 3.86 (s, 3H), 3.85-3.77 (m, 1H), 2.84-2.66 (m, 2H), 2.39 (s, 3H), 2.32-2.19 (m, 2H), 2.01 (s, 3H).

[0569] Example 34. Preparation of 1-(3-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminoquinazolin-6-yl)piperidin-1-yl)prop-2-en-1-one (final product 55)

[0570] First Step: tert-Butyl 3-(4-amino-8-bromoquinazolin-6-yl)piperidine-1-carboxylate (Intermediate Al l, 320.0 mg, 0.79 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 4.4 mL) under nitrogen protection, 7-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)- [1,2,4]triazolo[1,5-a]pyridine (Intermediate F9, 350.4 mg, 0.94 mmol), Pd(dppf)Cl2-CH2Cl2(64.2 mg, 0.079 mmol) and K2CO3(325.8 mg, 2.36 mmol) were added successively, and the mixture was stirred at 100 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (35 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give tert-butyl 3-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminoquinazolin-6-yl)piperidine-1-carboxylate (yellow solid, 390 mg, 86.8%). MS (ESI + m / z = 572.4 [M+H] + .

[0571] Step 2, 3: 1-(3-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminoquinolin-6-yl)piperidin-1-yl)prop-2-en-1-one was prepared following the procedure of Step 2, 3 of the synthesis of final product 145 from tert-butyl 3-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminquinolin-6-yl)piperidine-1-carboxylate and acrylic anhydride.

[0572] White solid, MS (ESI + m / z = 526.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 7.5 Hz, 1H), 8.48 - 8.37 (m, 2H), 8.18 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.92 - 7.73 (m, 4H), 7.49 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 7.4, 2.7 Hz, 1H), 7.04 - 6.97 (m, 1H), 6.97 - 6.80 (m, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.67 (t, J = 10.3 Hz, 1H), 4.58 (t, J = 14.4 Hz, 1H), 4.19 (t, J = 15.3 Hz, 1H), 3.12 (t, J = 13.2 Hz, 1H), 2.97 - 2.76 (m, 2H), 2.12 - 2.00 (m, 1H), 2.00 - 1.78 (m, 2H), 1.65 - 1.45 (m, 1H).

[0573] Examples 35-54. Preparation of final products 88, 90-93, 95-101, 103-108, 115, 118

[0574] Final products 88, 90-93, 95-101, 103-108, 115, 118 were prepared using the preparation method of final product 55 above from intermediates A11-A17, A19-A24, intermediates F2-F10 and commercially available compounds. The first step coupling condition can also be: Pd(dppf)Cl2, Cs2CO3, 1,4-dioxane, H2O, 100 °C.

[0575] Table 10. Intermediate raw materials, structures and characterization data in the preparation of final products 88, 90-93, 95-101, 103-108, 115, 118

[0576] Example 55. N-[4-amino-8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6- yloxyphenyl)quinazolin-6-yl]prop-2-enoyl (Final product 61)

[0577] First step: under nitrogen protection, 6-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (Intermediate Fl, 220.0 mg, 0.59 mmol) was dissolved in 1,4-dioxane (3 mL), water (0.3 mL), potassium phosphate (377 mg, 1.78 mmol), Pd(dppf)Cl2-CH2Cl2(43.3 mg, 0.06 mmol) and 8-bromo-6-nitroquinazolin-4-amine (Intermediate 8, 159.3 mg, 0.59 mmol) were added successively, and the mixture was stirred at 100 °C for 3 h. After the reaction was completed, the reaction solution was concentrated, and the obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 10) as the eluent to obtain 8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxyphenyl)-6-nitroquinazolin-4-amine (yellow solid, 170 mg, 66.2%). MS (ESI + )m / z = 434.1 [M+H] + .

[0578] Second step: under nitrogen protection, 8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6- yloxyphenyl)-6-nitroquinazolin-4-amine (170 mg, 0.39 mmol) was dissolved in methanol (2 mL), water (2 mL), iron powder (6.44 mg, 0.12 mmol) and ammonium chloride (104.8 mg, 1.96 mmol) were added successively, and the mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 10) as the eluent to obtain 8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxyphenyl)quinazolin-4,6-diamine (white solid, 130 mg, 82.2%). MS (ESI + )m / z = 404.1 [M+H] + .

[0579] Step 3: 8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxyphenyl)quinazoline-4,6- diamine (140 mg, 0.35 mmol) was dissolved in pyridine (3 mL), followed by the addition of EDCI . HCl (99.7 mg, 0.52 mmol) and acrylic acid (20 mg, 0.28 mmol) and stirred at room temperature for 1 h. After the reaction was completed, the resulting residue was isolated and purified by high performance liquid preparative chromatography (column type: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) / acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile 20% to 34% in 11 min; wavelength: 254-220 nm) to give N-[4-amino-8-(3-chloro-4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxyphenyl)quinazolin-6- yl]prop-2-enamide.

[0580] White solid, MS (ESI + )m / z = 458.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.00 - 7.88 (m, 3H), 7.73 - 7.68 (m, 2H), 7.66 - 7.59 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 6.58 - 6.42 (m, 1H), 6.39 - 6.28 (m, 1H), 5.83 (dd, J = 10.0, 2.1 Hz, 1H).

[0581] Example 56. Preparation of N-(4-amino-8-(3-chloro-4-(pyridin-3- ylmethoxy)phenyl)quinazolin-6-yl)acrylamide (final product 65)

[0582] Final product 65 was prepared according to the procedure for synthesizing final product 61, using 8-bromo-6-nitroquinazoline-4-amine (Intermediate 8) and Intermediate F6 as starting materials.

[0583] White solid, MS (ESI + )m / z = 432.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.74 (s, 1H), 8.63 - 8.55 (m, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.98 - 7.85 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.69 (s, 2H), 7.65 - 7.56 (m, 1H), 7.54 - 7.43 (m, 1H), 7.38 (d, J = 8.7 Hz, 1H), 6.51 (dd, J = 10.2, 17.1 Hz, 1H), 6.32 (d, J = 17.1 Hz, 1H), 5.88 - 5.78 (m, 1H), 5.35 (s, 2H).

[0584] Example 57. Preparation of N-(4-amino-8-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)quinazolin-6- yl)acrylamide (final product 66)

[0585] Final product 66 was prepared following the procedure for the synthesis of final product 61, starting from 8-bromo-6-nitroquinazolin-4-amine (Intermediate 8) and Intermediate F7.

[0586] White solid, MS (ESI + )m / z = 449.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.69 (s, 2H), 7.64 - 7.44 (m, 2H), 7.40 - 7.29 (m, 3H), 7.25 - 7.15 (m, 1H), 6.58 - 6.42 (m, 1H), 6.33 (d, J = 16.8 Hz, 1H), 5.83 (d, J = 10.0 Hz, 1H), 5.35 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -112.98.

[0587] Example 58. Preparation of l-(4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminoquinazolin-6-yl)piperazin-l-yl)prop-2-en-l-one (final product 94)

[0588] First Step: 4-(4-amino-3, 5-dibromo-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (Intermediate A18, 370.0 mg, 0.85 mmol), 7-(2-chloro-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy)- [1,2,4]triazolo[1,5-a]pyridine (Intermediate F9, 316.0 mg, 0.85 mmol) were used as starting materials to prepare 4-(4'-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-6-amino-5-bromo-3'-chloro- [1,1 '-biphenyl]-3-yl) piperazine-1 -carboxylic acid tert-butyl ester (yellow solid, 200 mg, 39.2%) according to the procedure for the first step of the synthesis of the final product 55. MS (ESI + )m / z = 601.1 [M+H] + .

[0589] Second Step: 4-(4'-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-6-amino-5-bromo-3'-chloro- [1,1 '-biphenyl]-3-yl) piperazine-1 -carboxylic acid tert-butyl ester (170.0 mg, 0.28 mmol) was dissolved in DMF (5 mL) under nitrogen protection, and then RuPhos Pd G3 (23.7 mg, 0.028 mmol), RuPhos (13.2 mg, 0.028 mmol) and zinc cyanide (39.9 mg, 0.34 mmol) were added successively. The reaction mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent to give 4-(4'-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-6-amino-3'-chloro-5-cyano- [1,1 '-biphenyl]-3-yl) piperazine-1 -carboxylic acid tert-butyl ester (white solid, 90 mg, 58.1 %). MS (ESI + )m / z = 546.2 [M+H] + .

[0590] Step 3: 4-(4'-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3'-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-[l,l'-biphenyl]-3-yl)piperazine-l- carboxylic acid tert-butyl ester (90.0 mg, 0.16 mmol) was dissolved in DMF-DMA (5 mL) and warmed to 100 °C for 1 h. After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure to give 4-(4'-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3'-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-[l,l'-biphenyl]-3-yl)piperazine-l- carboxylic acid tert-butyl ester (yellow oil, 90 mg, crude). This was used without purification in the next step. MS (ESI) m / z = 601.3 [M+H] + MS (ESI) m / z = 601.3 [M+H] + .

[0591] Step 4: 4-(4'-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3'-chloro-5-cyano-6-(((dimethylamino)methylene)amino)-[l,l'-biphenyl]-3-yl)piperazine-l- carboxylic acid tert-butyl ester (90.0 mg, 0.15 mmol) was dissolved in acetic acid (3 mL) and ammonium acetate (23.1 mg, 0.30 mmol) was added. The reaction was warmed to 80 °C and stirred overnight. After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol / dichloromethane (0-20%) to give 4-(8-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrimidin-6-yl)piperazine-l-carboxylic acid tert-butyl ester (yellow solid, 13 mg, 15.2%). MS (ESI) m / z = 573.1 [M+H] + MS (ESI) m / z = 573.1 [M+H] + .

[0592] Step 5, 6: 1-(4-(8-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrimidin-6-yl)piperazin-l-yl)prop-2-en-l-one was prepared from 4-(8-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrimidin-6-yl)piperazine-l-carboxylic acid tert-butyl ester and acrylic anhydride following the procedure described in Step 2, 3 of the synthesis of final product 145.

[0593] White solid, MS (ESI) m / z = 527.2 [M+H] + MS (ESI) m / z = 527.2 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 7.7 Hz, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.79 - 7.65 (m, 2H), 7.65 - 7.57 (m, 2H), 7.56 - 7.43 (m, 2H), 7.10 (dd, J = 7.5, 2.7 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 16.7, 10.6 Hz, 1H), 6.15 (dd, J = 16.8, 2.4 Hz, 1H), 5.77 - 5.67 (m, 1H), 3.80 - 3.70 (m, 4H), 3.47 - 3.39 (m, 2H), 3.31 - 3.19 (m, 2H).

[0594] Example 59. Preparation of l-(4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)-4-fluoropiperidin-l-yl)prop-2-en-l-one trifluoroacetate salt (final product 109)

[0595] First Step: l-(2-amino-5-bromo-3-iodophenyl)ethanone (4.5 g, 13.24 mmol) and 7-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-[l,2,4]triazolo[l,5- a]pyridine (Intermediate F9, 5.9 g, 15.88 mmol) were used as starting materials to synthesize final product 55

[0596] l-(2-amino-5-bromo-3-iodophenyl)ethanone (4.5 g, 13.24 mmol) and 7-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-[l,2,4]triazolo[l,5- a]pyridine (Intermediate F9, 5.9 g, 15.88 mmol) were used as starting materials to synthesize final product 55 + m / z = 457.0 [M+H] + .

[0597] Second step: under nitrogen protection, dissolve 1-(4'-([1,2,4]triazolo[1,5- a]pyridin-7-yloxy)-2-amino-5-bromo-3'-chloro-[1,1'-biphenyl]-3-yl)ethanone (4.0 g, 8.74 mmol) in methanol (60 mL), add ammonium acetate (1.3 g, 17.48 mmol), copper chloride (235.0 mg, 1.75 mmol) and TBHP (4.7 g, 52.43 mmol) in sequence, warm up to 60 °C and stir for 5 h. After the reaction is completed, cool to room temperature, concentrate the reaction solution under reduced pressure, and separate the obtained residue by silica gel column chromatography with ethyl acetate / petroleum ether (0-92%) as eluent gradient to obtain 8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-bromo-4- methylquinazoline (yellow solid, 2 g, 49.0%). MS (ESI + )m / z = 466.0 [M+H] + .

[0598] Third step: under nitrogen protection, dissolve 8-(4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)-3-chlorophenyl)-6-bromo-4-methylquinazoline (150.0 mg, 0.32 mmol) in 1,4- dioxane (4 mL), add Pd(dppf)Cl2·CH2Cl2(23.5 mg, 0.032 mmol), K2CO3(111.0 mg, 0.80 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (119.3 mg, 0.39 mmol) in sequence, warm up to 100 °C and stir for 1 h. After the reaction is completed, cool to room temperature, add water (10 mL) to the reaction solution, extract the mixture with ethyl acetate (10 mL x 3), dry the combined organic phases with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the obtained residue by silica gel column chromatography with methanol / dichloromethane (0-6%) as eluent gradient to obtain tert-butyl 4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methylquinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yellow solid, 120 mg, 65.6%). MS (ESI + )m / z = 569.2 [M+H] + .

[0599] Fourth Step: tert-Butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (500.0 mg, 0.88 mmol) was dissolved in a mixture of isopropanol and dichloromethane (5 / 1 v / v, 12 mL) under nitrogen protection, and manganese tris(biphenylmethylene) (159.4 mg, 0.26 mmol) was added. The temperature was lowered to -5 °C, and phenylsilane (475.4 mg, 4.39 mmol) was added. The oxygen was replaced with nitrogen, and the mixture was stirred at -5 °C for 1 h. After the reaction was completed, the temperature was raised to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (0-8%) as the eluent to give tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (yellow oil, 160 mg, 31.0%). MS (ESI) m / z = 587.1 [M+H] + )m / z = 589.2 [M+H] + .

[0600] Fifth Step: tert-Butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (150.0 mg, 0.26 mmol) was dissolved in DCM (4 mL) under nitrogen protection, and BAST (113.1 mg, 0.51 mmol) was added. The temperature was lowered to -78 °C, and the mixture was stirred at -78 °C for 1 h. After the reaction was completed, the temperature was raised to room temperature, and the pH of the reaction mixture was adjusted to 7 with aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel using methanol / dichloromethane (0-5%) as the eluent to give tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methylquinolin-6-yl)-4-fluoropiperidine-l-carboxylate (pale yellow oil, 100 mg, 66.4%). MS (ESI) m / z = 589.2 [M+H] + )m / z = 589.2 [M+H] + .

[0601] Step 6, 7: 1-(4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)piperidin-1-yl)propan-2- en-1-one was prepared from 4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7- yloxy)-3-chlorophenyl)-4-methylquinolin-6-yl)-4-fluoropiperidine-1- carboxylate and acrylic anhydride following the procedure for the synthesis of the second and third steps of the final product 145.

[0602] White solid, MS (ESI + m / z = 543.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.01 (d, J = 7.5 Hz, 1H), 8.46 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.4, 2.1 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 7.4, 2.7 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 16.7, 10.4 Hz, 1H), 6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.74 (dd, J = 10.4, 2.5 Hz, 1H), 4.62 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 13.8 Hz, 1H), 3.47 (t, J = 13.2 Hz, 1H), 3.10 - 2.91 (m, 4H), 2.42 - 2.25 (m, 2H), 2.18 - 2.04 (m, 2H).

[0603] Example 60. Preparation of 1-(4-(8-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-4- methylquinolin-6-yl)piperazin-1-yl)propan-2-en-1-one (final product 111)

[0604] First Step: 5-(4-(6-bromo-4-methylquinazolin-8-yl)-2-chlorophenoxy)benzo[d]thiazole (white solid, 340 mg, 25.6%) was prepared following the procedure of the first step of the synthesis of final product 55 starting from 6-bromo-8-iodo-4-methylquinazoline (intermediate 15, 960.0 mg, 2.75 mmol) and 5-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)benzo[d]thiazole (intermediate F3, 1.3 g, 3.30 mmol). MS (ESI) m / z = 483.9 [M+H] + m / z = 483.9 [M+H] + .

[0605] Second Step: 4-(8-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-4-methylquinazolin-6- yl)piperazine-l -carboxylate (brown solid, 285 mg, 68.8%) was prepared following the procedure of the second step of the synthesis of final product 145 starting from 5-(4-(6-bromo-4- methylquinazolin-8-yl)-2-chlorophenoxy)benzo[d]thiazole (340.0 mg, 0.70 mmol) and tert- butyl piperazine-l -carboxylate (157.4 mg, 0.85 mmol). MS (ESI) m / z = 588.1 [M+H] + m / z = 588.1 [M+H] + .

[0606] Third Step, Fourth Step: l-(4-(8-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-4- methylquinazolin-6-yl)piperazin-l-yl)prop-2-en-l-one was prepared following the procedure of the second and third steps of the synthesis of final product 145 starting from 4-(8-(4-(benzo[d]thiazol-5-yloxy)-3-chlorophenyl)-4-methylquinazolin-6-yl)piperazine-l-carboxylate and acrylic anhydride.

[0607] pale yellow solid, MS (ESI) + m / z = 542.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.91 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.98-7.89 (m, 2H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.38-7.22 (m, 3H), 6.89 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.76 (s, 4H), 3.46 (s, 4H), 2.88 (s, 3H).

[0608] Example 61. Preparation of 1-(4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)piperazin-1-yl)prop-2-en-1-one (final product 112)

[0609] First Step: 8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-bromo-4- methylquinoline (1.6 g, 3.43 mmol) was dissolved in super dry DMA (6 mL), cooled to 0 °C, and DABCO (769.1 mg, 6.86 mmol), zinc powder (43.5 mg, 0.69 mmol) and Ni(4-tBustb)3(320.9 mg, 0.34 mmol) were added successively, and stirred at 0 °C for 5 min. Then tert-butyl piperazine-1-carboxylate (1.4 g, 6.86 mmol) was added, and the temperature was raised to 60 °C and stirred for 24 h. After the reaction was completed, the temperature was cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-42%) as eluent gradient to give tert-butyl 4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methylquinolin-6-yl)piperazine-1-carboxylate (yellow solid, 800 mg, 40.7%). MS (ESI + m / z = 572.1 [M+H] + .

[0610] Second and third steps: 1-(4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)piperazin-1-yl)prop-2-en-1-one was prepared from 4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methylquinolin-6- yl)piperazine-1-carboxylic acid tert-butyl ester (800.0 mg, 1.40 mmol) and acrylic anhydride following the procedure for the second and third steps of the synthesis of the final product 145.

[0611] pale yellow solid, MS (ESI + m / z = 526.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.5 Hz, 1H), 8.93 (s, 1H), 8.44 (s, 1H), 8.03 - 7.93 (m, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.90 (dd, J = 16.9, 10.5 Hz, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 3.78 (s, 4H), 3.51 - 3.45 (m, 4H), 2.90 (s, 3H).

[0612] Example 62. Preparation of 1-(5-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one (final product 113)

[0613] 1-(5-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methylquinolin-6- yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)prop-2-en-1-one was prepared from 8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-bromo-4-methylquinoline, tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate and acrylic anhydride following the procedure for the second to fourth steps of the synthesis of the final product 111.

[0614] yellow solid, MS (ESI + m / z = 552.2 [M+H]+ . 1 H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J = 7.5 Hz, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.02 (t, J = 2.2 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.74 - 7.69 (m, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 7.5, 2.7 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.93 - 6.55 (m, 1H), 6.27 - 6.10 (m, 1H), 5.79 - 5.65 (m, 1H), 4.84 - 4.56 (m, 2H), 3.96 - 3.55 (m, 4H), 2.86 (s, 3H), 2.14 - 1.84 (m, 4H).

[0615] Example 63. Preparation of l-(5-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methylquinolin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-l-one (final product 114)

[0616] l-(5-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methylquinolin-6- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-l-one was prepared from 8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6-bromo-4-methylquinoline, tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and acrylic anhydride following the procedure for the preparation of final product 111, second to fourth steps.

[0617] Yellow solid, MS (ESI + )m / z = 538.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d J = 7.4 Hz, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.61 (dd, J = 7.2, 2.6 Hz, 1H), 7.53 (dd, J = 8.4, 1.4 Hz, 1H), 7.13 (dd, J = 7.5, 2.7 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.85 - 6.37 (m, 1H), 6.21 - 6.07 (m, 1H), 5.75 - 5.59 (m, 1H), 5.07 (d, J = 7.2 Hz, 1H), 4.96 (d, J = 13.6 Hz, 1H), 3.83 - 3.63 (m, 2H), 3.51 (s, 1H), 3.36 (s, 1H), 2.86 (s, 3H), 2.15 - 1.97 (m, 2H).

[0618] Example 64. Preparation of l-(4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminopyrido[3,4-d]pyrimidin-6-yl)piperidin-l-yl)prop-2-en-l-one (final product 119)

[0619] First Step: 8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-6- chloropyrido[3,4-d]pyrimidin-4-amine (yellow solid, 170 mg, 69.3%) was prepared following the method of first step for the synthesis of final product 55, starting from 8-bromo-6-chloropyrido[3,4-d]pyrimidin-4-amine (intermediate 10, 150.0 mg, 0.58 mmol) and 7-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)- [l,2,4]triazolo[l,5-a]pyridine (intermediate F9, 214.8 mg, 0.58 mmol). MS (ESI + m / z = 424.0 [M+H] + .

[0620] Second step: under nitrogen, 8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-6-chloropyrido[3,4-d]pyrimidin-4-amine (170.0 mg, 0.40 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 5 mL), Pd(dppf)Cl2-CH2Cl2(32.7 mg, 0.040 mmol), K2CO3(166.1 mg, 1.20 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (148.7 mg, 0.48 mmol) were added successively, and the mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-15%) as eluent to give tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (yellow solid, 130 mg, 57.0%). MS (ESI + m / z = 571.1 [M+H] + .

[0621] Third step: under nitrogen, tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminopyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (90.0 mg, 0.16 mmol) was dissolved in ethyl acetate (10 mL), platinum dioxide monohydrate (77.3 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 2 h under hydrogen replacement. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrido[3,4-d]pyrimidin-6-yl)piperidine-l-carboxylate (yellow solid, 30 mg, crude). MS (ESI + m / z = 573.1 [M+H] + .

[0622] Fourth and fifth steps: 1-(4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminopyrido[3,4-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one was prepared from 4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- aminopyrido[3,4-d]pyrimidin-6-yl)piperidine-1-carboxylate tert-butyl (30.0 mg, 0.052 mmol) and acrylic anhydride following the procedure for the second and third steps of the synthesis of the final product 145.

[0623] White solid, MS (ESI + m / z = 527.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.04 - 8.95 (m, 1H), 8.58 - 8.51 (m, 2H), 8.45 (s, 1H), 8.33 (dd, J = 8.6, 2.1 Hz, 1H), 8.28 - 8.09 (m, 2H), 8.06 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.17 - 7.08 (m, 2H), 6.90 (dd, J = 16.7, 10.4 Hz, 1H), 6.14 (dd, J = 16.7, 2.5 Hz, 1H), 5.70 (dd, J = 10.4, 2.5 Hz, 1H), 4.63 (d, J = 12.9 Hz, 1H), 4.25 (d, J = 13.4 Hz, 1H), 3.30 - 3.08 (m, 2H), 2.84 (t, J = 12.2 Hz, 1H), 2.14 - 2.02 (m, 2H), 1.82 - 1.62 (m, 2H).

[0624] Example 65. Preparation of 1-(4-(8-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminopyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2- en-1-one (final product 120)

[0625] Prepared from tert-butyl 4-(8-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-aminopyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate and acrylic anhydride following the procedure for the synthesis of the final product 145, second and third steps.

[0626] White solid, MS (ESI + m / z = 525.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.1 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.41 - 8.08 (m, 4H), 7.54 (d, J = 8.6 Hz, 1H), 7.17 - 7.07 (m, 2H), 7.06 - 6.76 (m, 2H), 6.17 (d, J = 17.1 Hz, 1H), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 4.42 (s, 1H), 4.32 (s, 1H), 3.93 - 3.76 (m, 2H), 2.75 (d, J = 17.7 Hz, 2H).

[0627] Example 66. Preparation of l-(5-(7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidin-l-yl)prop-2- en-l-one (final product 125)

[0628] First step: tert-Butyl 2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)piperidine-1-carboxylate (Intermediate A7, 800.0 mg, 2.42 mmol) was dissolved in 1,4-dioxane (10 mL) under nitrogen protection, 7-(4-bromo-2-chlorophenoxy)- [1,2,4]triazolo[1,5-a]pyridine (Intermediate C14, 785.8 mg, 2.42 mmol), (SP-4-1)-(1,3- bis(2,6-bis(1-ethylpropyl)phenyl)-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene)dichloro(2-methylpyridine)palladium (203.4 mg, 0.24 mmol) and Cs2CO3(1.6 g, 4.84 mmol) were added in turn, and the mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (0-15%) as eluent to give tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate (yellow solid, 410 mg, 29.5%). MS (ESI) m / z = 574.2 [M+H] + . + .

[0629] Second step, third step: 1-(5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidin-1-yl)prop-2- en-1-one was prepared from tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidine-1- carboxylate and acrylic anhydride according to the method for synthesizing the second step, third step of the final product 145.

[0630] Fourth step: 1-(5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidin-1-yl)prop-2-en-1-one was separated by chiral preparative chromatography column (column type: CHIRALPAK IK 2*25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.5% 2M NH3·MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 40% mobile phase B) to give two cis products, the specific configuration of which was unknown.

[0631] First eluting product

[0632] White solid, MS (ESI + m / z = 528.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 7.5 Hz, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 8.38 - 8.31 (m, 1H), 8.17 - 8.03 (m, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 7.5, 2.7 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.95 - 6.78 (m, 1H), 6.11 (t, J = 14.7 Hz, 1H), 5.73 - 5.60 (m, 1H), 4.98 - 4.61 (m, 1H), 4.49 - 4.09 (m, 1H), 3.27 - 2.98 (m, 2H), 2.82 (d, J = 14.1 Hz, 3H), 2.11 - 1.88 (m, 2H), 1.88 - 1.68 (m, 2H), 1.32 - 1.15 (m, 3H).

[0633] Second eluting product

[0634] White solid, MS (ESI + m / z = 528.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 7.5 Hz, 1H), 8.74 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.17 - 8.04 (m, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 7.5, 2.7 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.95 - 6.78 (m, 1H), 6.11 (t, J = 15.5 Hz, 1H), 5.78 - 5.60 (m, 1H), 4.97 - 4.01 (m, 2H), 3.26 - 2.97 (m, 2H), 2.82 (d, J = 14.1 Hz, 3H), 2.13 - 1.59 (m, 4H), 1.35 - 1.17 (m, 3H).

[0635] Example 67. Preparation of 1-(5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop- 2-en-1-one (final product 126)

[0636] Step 1: Under nitrogen protection, tert-butyl 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (intermediate A4, 700.0 mg, 2.23 mmol) was dissolved in DMF (10 mL), and 7-(2-chloro-4-iodophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (intermediate C2, 910.0 mg, 2.45 mmol), CuI (424.0 mg, 2.23 mmol), K2CO3 (615.5 mg, 4.45 mmol), and (1S,2S)-1,2-cyclohexanediamine (633.4 mg, 4.45 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 1 h. After the reaction was complete and cooled to room temperature, water (20 mL) was added to the reaction solution, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was dried to obtain tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H-pyrrolidinyl[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yellow solid, 600 mg, 48.3%). MS (ESI) + m / z = 559.1 [M+H] + .

[0637] Steps 2 and 3: Using tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H-pyrrolidinyl[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-carboxylate and acryloyl chloride as raw materials, 1-(5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H-pyrrolidinyl[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was prepared according to the method of Steps 3 and 4 for synthesizing final product 6.

[0638] White solid, MS (ESI) + m / z = 512.2[M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.5 Hz, 1H), 8.78 (s, 1H), 8.44 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.23 - 8.00 (m, 2H), 7.71 - 7.59 (m, 1H), 7.12 (dd, J = 7.5, 2.7 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.03 - 6.83 (m, 1H), 6.27 - 6.00 (m, 2H), 5.74 (d, J = 12.3 Hz, 1H), 4.50 - 4.31 (m, 2H), 3.87 - 3.69 (m, 2H), 2.72 (s, 3H), 2.46 - 2.23 (m, 2H).

[0639] Example 68.

[0640] Preparation of l-(4-((7-(3-chloro-4-(quinoxaline-6-yloxy)phenyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)oxy)piperidin-l-yl)prop-2-en-l-one (Final Product 128)

[0641] First Step: 3-chloro-4-(quinoxaline-6-yloxy)aniline (product from second step of Preparation Intermediate C8, 2.7 g, 9.94 mmol) was dissolved in n-butanol (20 mL), 4-chloro-6-methylpyrimidine-5-carboxylic acid ethyl ester (Intermediate 11, 2.0 g, 9.94 mmol) and DIEA (3.9 g, 29.81 mmol) were added successively, and the mixture was stirred at 90 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel with 20% ethyl acetate in petroleum ether as eluent to give 4-((3-chloro-4-(quinoxaline-6-yloxy)phenyl)amino)-6-methylpyrimidine-5-carboxylic acid ethyl ester (brown oil, 1.6 g, 36.9%). MS (ESI m / z = 436.1 [M+H] + m / z = 436.1 [M+H] + .

[0642] Second Step: 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)amino)-6-methylpyrimidine-5- carboxylic acid ethyl ester (1.6 g, 3.67 mmol) was dissolved in DMF (15 mL), cooled to 0 °C, NaH (60%, 367.1 mg, 9.18 mmol) was added, stirred at 0 °C for 0.5 h. Then 2-bromoethyl acetate (1.2 g, 7.34 mmol) was added, the reaction was stirred at room temperature for 1 h. After the reaction was completed, water (30 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)(2-ethoxy-2-oxoethyl)amino)-6-methylpyrimidine-5-carboxylic acid ethyl ester (brown oil, 1.6 g, crude).

[0643] Third Step: 4-((3-chloro-4-(quinoxalin-6-yloxy)phenyl)(2-ethoxy-2-oxoethyl)amino)-6- methylpyrimidine-5-carboxylic acid ethyl ester (1.6 g, 3.07 mmol) was dissolved in THF (15 mL), potassium tert-butoxide (687.9 mg, 6.13 mmol) was added, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography eluted with methanol / dichloromethane (5%) to give 7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-hydroxy-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (yellow solid, 1.5 g, 85.8% yield for two steps). MS (ESI + m / z = 476.1 [M+H] + .

[0644] Fourth step: 7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-5-hydroxy-4-methyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1.5 g, 3.15 mmol) was dissolved in DMF (15 mL), K2CO3 (871.3 mg, 6.30 mmol) and tert-butyl 4-bromopiperidine-1- carboxylate (4.2 g, 15.76 mmol) were added successively, and the mixture was stirred at 70 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with methanol / dichloromethane (5%) as the eluent to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (brown oil, 1.6 g, 77.3%). MS (ESI) m / z = 659.2 [M+H] + m / z = 631.1 [M+H] + .

[0645] Fifth step: 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (800.0 mg, 1.21 mmol) was dissolved in a mixture of methanol and water (2 / 1 v / v, 12 mL), and sodium hydroxide (242.7 mg, 6.07 mmol) was added. The mixture was stirred at 50 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The aqueous phase was adjusted to pH 3 with hydrochloric acid (1 M), and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (brown oil, 450 mg, 58.7%). MS (ESI) m / z = 631.1 [M+H] + m / z = 631.1 [M+H] + .

[0646] Sixth step: 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (450.0 mg, 0.71 mmol) was dissolved in DMAc (5 mL) and stirred at 140 °C under nitrogen overnight. After the reaction was completed, the reaction was cooled to room temperature, water (10 mL) was added to the reaction, the mixture was extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with gradient elution (0-50%) to obtain 4-((7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (yellow solid, 150 mg, 35.8%). MS (ESI + )m / z = 587.2 [M+H] + .

[0647] Seventh and eighth steps: 1-(4-((7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxy)piperidin-1-yl)prop-2-en-1-one was prepared according to the method for synthesizing the final product 6, third and fourth steps, using 4-((7-(3-chloro-4-(quinoxalin-6-yloxy)phenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester and acryloyl chloride as raw materials.

[0648] Yellow solid, MS (ESI + )m / z = 541.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.93 - 8.83 (m, 2H), 8.73 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.11 (dd, J = 8.8, 2.8 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J = 9.2, 2.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 16.8, 10.4 Hz, 1H), 6.12 (dd, J = 16.4, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.70 - 4.55 (m, 1H), 3.90 - 3.74 (m, 2H), 3.65 - 3.48 (m, 2H), 2.79 (s, 3H), 2.08 (brs, 2H), 1.80 (brs, 2H).

[0649] Examples 69-71. Preparation of end products 129-131

[0650] End products 129-131 were prepared using the procedure for the synthesis of end product 128, starting from commercially available ethyl 4-chloro-6-methylpyrimidine-5-carboxylate and the product from the second step of the synthesis of intermediates C2, C5, C12, as detailed in Table 11.

[0651] Table 11. Raw materials, structures and characterization data required for the preparation of end products 129-131

[0652] Example 72. Preparation of l-(4-((7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidin-l-yl)prop-2-en- l-one (end product 133)

[0653] l-(4-((7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidin-l-yl)prop-2-en-l-one was prepared following the procedure for the synthesis of end product 126, starting from tert-butyl 4-((4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)piperidine-l-carboxylate (Intermediate A8), 7-(2-chloro-4-iodophenoxy)-[l,2,4]triazolo[l,5-a]pyridine (Intermediate C2) and acryloyl chloride.

[0654] White solid, MS (ESI+ m / z = 528.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 7.5 Hz, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 2.7 Hz, 1H), 8.05 (dd, J = 9.0, 2.7 Hz, 1H), 7.90 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 7.5, 2.7 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 16.8, 10.5 Hz, 1H), 6.08 (dd, J = 16.8, 2.4 Hz, 1H), 5.65 (dd, J = 10.5, 2.4 Hz, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.06 (d, J = 13.2 Hz, 1H), 3.04 (t, J = 12.6 Hz, 1H), 2.81 (s, 3H), 2.80 - 2.54 (m, 3H), 2.04 - 1.87 (m, 1H), 1.87 - 1.75 (m, 2H), 1.25 - 1.06 (m, 2H).

[0655] Example 73. Preparation of (S)-1-(2-(4-amino-1-(3-chloro-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)pyrrolidin-1-yl)but-2-yn-1- one (final product 135)

[0656] First step: (S)-2-(4-amino-1-(3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5- yl)oxy)phenyl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)pyrrolidine-1-carbaldehyde (Intermediate E14, 300.0 mg, 0.61 mmol) was dissolved in ethanol (2 mL), hydrochloric acid aqueous solution (6 M, 2.0 mL, 12.27 mmol) was added, and the mixture was stirred at reflux for 1 h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 9 with sodium bicarbonate, and the mixture was extracted with a dichloromethane / methanol mixture (10 / 1, v / v, 5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-1-(3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3-(pyrrolidin-2-yl)-1H- pyrazol[3,4-d]pyrimidin-4-amine (pale yellow solid, 200 mg, crude). MS (ESI + m / z = 461.1 [M+H] + .

[0657] Step 2: (S)-1-(3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3- (pyrrolidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200.0 mg, 0.43 mmol) was dissolved in DMF (2 mL), 2-butynoic acid (109.4 mg, 1.30 mmol) was added, followed by dropwise addition of T3P (276.1 mg, 0.87 mmol) and triethylamine (131.7 mg, 1.30 mmol), and stirred at room temperature for 1 h. After the reaction was completed, water (6 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel thin layer chromatography plate with methanol / dichloromethane (10%) as the developing agent to obtain (S)-1-(2-(4-amino-1-(3-chloro-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyrrolidin-1-yl)but-2-yn-1- one.

[0658] White solid, MS (ESI + )m / z = 527.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.04 (dd, J = 8.8, 2.8 Hz, 1H), 8.00 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 5.69-5.58 (m, 1H), 4.07-3.93 (m, 1H), 3.87 (s, 3H), 3.85-3.77 (m, 1H), 2.88-2.62 (m, 2H), 2.37-2.14 (m, 2H), 2.01 (s, 3H).

[0659] Example 74. Preparation of (S)-1-(2-(4-amino-1-(3-methyl-4-((1-methyl-1H- benzo[d]imidazol-5-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyrrolidin-1-yl)but-2-yn-1- one (final product 136)

[0660] (S)-1-(2-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)pyrrolidin-1-yl)butan-2-yne-1-ketone was prepared from (S)-2-(4-amino-1-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)pyrrolidine-1-carbaldehyde (Intermediate E15) and 2-butyne acid following the procedure for the synthesis of the final product 135.

[0661] White solid, MS (ESI + m / z = 507.2 [M+H] + . 1 H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.99-7.91 (m, 2H), 7.80 (dd, J = 8.7, 2.4 Hz, 1H), 7.38-7.30 (m, 2H), 7.06 (dd, J = 8.7, 2.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.63 (d, J = 6.3 Hz, 1H), 4.03-3.92 (m, 1H), 3.85 (s, 3H), 3.82-3.75 (m, 1H), 2.86-2.61 (m, 2H), 2.37 (s, 3H), 2.35-2.14 (m, 2H), 2.00 (s, 3H).

[0662] Example 75. Preparation of 1-5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidin-1-yl)prop-2-en-1- one (Final product 140)

[0663] First Step: tert-Butyl 5-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate (Intermediate A6, 400.0 mg, 0.89 mmol) was dissolved in 1,4-dioxane (5 mL) under nitrogen protection, 7-(4-bromo-2- chlorophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (Intermediate C14, 345.0 mg, 1.06 mmol), (SP-4-1)-(1,3-bis(2,6-bis(1-ethylpropyl)phenyl)-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene)dichloro(2-methylpyridine)palladium (74.4 mg, 0.089 mmol) and Cs2CO3(865.8 mg, 2.66 mmol) were added in turn, and the mixture was stirred at 100 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as eluent gradient to give tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-((4- methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate (yellow solid, 200 mg, 34.3%). MS (ESI) m / z = 695.2 [M+H] + + .

[0664] Second Step, Third Step: The crude product was prepared according to the method for synthesizing the final product 4 with tert-butyl 5-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-((4- methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpiperidine-1-carboxylate and acrylic anhydride as raw materials. The crude product was separated and purified by high-pressure liquid preparative chromatography (column type: YMC Triart C18 Column, 30*75 mm, 3 μm; mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 6 min of mobile phase B from 36% to 47%; wavelength: 254 / 220 nm) to give two products (white solid) in cis and trans forms. The cis product was separated by chiral preparative chromatography (column type: CHIRALPAK IA 2*25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.5% 2M NH3·MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 60% mobile phase B; wavelength: 220 / 254 nm) to give two products, the specific R or S configuration of which was unknown.

[0665] First eluted product ​

[0666] White solid, MS (ESI + m / z = 529.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 5.7 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 14.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 7.5, 2.7 Hz, 1H), 7.02 (s, 1H), 6.99 - 6.76 (m, 3H), 6.23 - 6.02 (m, 1H), 5.79 - 5.59 (m, 1H), 4.93 - 3.95 (m, 2H), 3.21 - 2.64 (m, 2H), 2.04 - 1.79 (m, 3H), 1.76 - 1.55 (m, 1H), 1.32 (d, J = 6.7 Hz, 2H), 1.27 - 1.16 (m, 1H).

[0667] Second eluting product

[0668] White solid, MS (ESI + m / z = 529.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 5.7 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 14.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 7.5, 2.7 Hz, 1H), 7.02 (s, 1H), 6.99 - 6.76 (m, 3H), 6.23 - 6.02 (m, 1H), 5.79 - 5.59 (m, 1H), 4.93 - 3.95 (m, 2H), 3.21 - 2.64 (m, 2H), 2.04 - 1.79 (m, 3H), 1.76 - 1.55 (m, 1H), 1.32 (d, J = 6.7 Hz, 2H), 1.27 - 1.16 (m, 1H).

[0669] Example 76. Preparation of 1-(3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one (Final Product 145, Final Product 146)

[0670] Step 1 : tert-Butyl 3-(7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (300.0 mg, 0.54 mmol) was dissolved in DCM (1.5 mL), cooled to 0 °C, TFA (1.5 mL) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give 7-(2-chloro-4-(4-methyl-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenoxy)- [l,2,4]triazolo[l,5-a]pyridine (brown oil, 310 mg, crude). MS (ESI + )m / z = 460.1 [M+H] + .

[0671] Step 2: tert-Butyl 3-(7-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- chlorophenyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (300.0 mg, 0.54 mmol) was dissolved in DCM (1.5 mL), cooled to 0 °C, TFA (1.5 mL) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give 7-(2-chloro-4-(4-methyl-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenoxy)- [l,2,4]triazolo[l,5-a]pyridine (brown oil, 310 mg, crude). MS (ESI + )m / z = 460.1 [M+H] + .

[0672] Step 3: 7-(2-chloro-4-(4-methyl-5-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (300.0 mg, 0.65 mmol) was dissolved in THF (5 mL), triethylamine (198.0 mg, 1.96 mmol) was added, and acrylic anhydride (41.1 mg, 0.33 mmol) was added dropwise slowly. The mixture was stirred at room temperature for 0.5 h. After the reaction was completed, saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by high-pressure preparative liquid chromatography (column type: XBridge Prep C18 OBD Column, 19 x 250 mm, 5 μm; mobile phase: acetonitrile / 10 mmol / L aqueous ammonium bicarbonate solution; flow rate: 25 mL / min; gradient: 31%-56% in 10 min) to give 1-(3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one.

[0673] Step 4: 1-(3-(7-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was separated by chiral preparative chromatography column (column type: CHIRALPAK IK 2*25 cm, 5 μm; mobile phase A: t-butyl methyl ether (0.5% 2M NH3·MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30% mobile phase B) to give two products, the specific R or S configuration of which was unknown.

[0674] First eluted product

[0675] White solid, MS (ESI + m / z = 514.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.4 Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.10 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 7.5, 2.7 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 7.01 - 6.83 (m, 1H), 6.24 - 6.07 (m, 1H), 5.79 - 5.63 (m, 1H), 4.88 - 4.48 (m, 1H), 4.46 - 4.10 (m, 1H), 3.22 - 3.04 (m, 2H), 2.92 - 2.79 (m, 3H), 2.74 - 2.60 (m, 1H), 2.19 (d, J = 12.7 Hz, 1H), 2.00 - 1.79 (m, 2H), 1.70 - 1.50 (m, 1H).

[0676] Second eluting product

[0677] White solid, MS (ESI + )m / z = 514.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 7.4 Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.10 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 7.5, 2.7 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 7.01 - 6.83 (m, 1H), 6.24 - 6.07 (m, 1H), 5.79 - 5.63 (m, 1H), 4.88 - 4.48 (m, 1H), 4.46 - 4.10 (m, 1H), 3.22 - 3.04 (m, 2H), 2.92 - 2.79 (m, 3H), 2.74 - 2.60 (m, 1H), 2.19 (d, J = 12.7 Hz, 1H), 2.00 - 1.79 (m, 2H), 1.70 - 1.50 (m, 1H).

[0678] Example 77-79. Preparation of final products 121-123

[0679] The end products 121-123 were prepared using the preparation method of the end product 145 above, using intermediates A9-A10, intermediates C13-C14, C20 and commercially available compounds as raw materials, as shown in Table 12. The conditions of the second step of the deprotection reaction can also be: TFA, H2O, 80°C or TFA, DCM, r.t.

[0680] Table 12. Structure of end products 121-123, raw materials of intermediates required for preparation and characterization data

[0681] Experimental Example 1 Cell proliferation inhibition experiment

[0682] CellTiter-Glo TM The CellTiter-Glo® Live Cell Assay Kit uses luciferase as a detector, and luciferase needs the participation of ATP in the luminescence process. Add CellTiter-Glo® reagent to the cell culture medium, measure the luminescence value, and the light signal is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by detecting the ATP content using the CellTiter-Glo® kit, the proliferation of cells can be detected. TM

[0683] In this experiment, the Celltiter-Glo (CTG) method was used to measure the proliferation inhibition effect of the compounds prepared in the foregoing on the tumor cell line HER2 775-776insYVMA Ba / F3 cell line, and the 50% inhibition concentration IC 50 .

[0684] 1. Experimental design

[0685] The compounds were determined on the selected cells, and a solvent control was set, and a total of 9 concentrations were detected, 2 replicate wells for each concentration.

[0686] 2. Reagents and consumables

[0687] 3. Experimental process

[0688] 3.1 Cell culture

[0689] a) All cells were cultured according to the recommended method of ATCC. The cells in the logarithmic growth phase were harvested. The cell viability was detected to ensure that the cell viability was more than 90%.

[0690] b) Cell culture medium: RPMI1640, 10% FBS, 1% P / S. Adjust the cell concentration, and add 95 μL of cell suspension to the 96-well plate, respectively.

[0691] c) Cell culture environment: cultured at 37°C, 5% CO2, 95% humidity.​

[0692] 3.2 Drug dilution

[0693] a) Drug stock solution: Drug was dissolved in DMSO to make 10 mM DMSO stock solution.

[0694] b) Drug storage: Drug DMSO stock solution was stored in a short-term (up to 3 months) at room temperature in a desiccator. The remaining drug was stored at -20 °C for a long time.

[0695] c) Preparation of 20X drug solution: 2 μL of drug stock solution was added to 98 μL of cell culture medium.

[0696] 3.3 Drug addition

[0697] a) All drugs were tested on HER2 775_776insYVMA Ba / F3 cell line (cultured in RPMI-1640 + 10% FBS + 1% P / S medium) and FL-EGFR-WT Ba / F3 cell line (cultured in RPMI-1640 + 10% FBS + 1% P / S + EGF medium) starting from 1 μM and 10 μM concentration respectively, 3-fold dilution, 9 concentration gradients.

[0698] b) Preparation of positive control, DMSO blank control.

[0699] c) 5 μL of 20X drug solution was added to each well of the 96-well plate seeded with cells, 2 replicates were set for each drug concentration.

[0700] d) The cells in the 96-well plate with added drugs were incubated at 37 °C, 5% CO2, 95% humidity for 72 hours, and then CTG analysis was performed.

[0701] 3.4 End-point plate reading

[0702] a) Thaw the CTG reagent, add 50 μL of CTG solution to each well, and shake well.

[0703] b) Place the cell plate at room temperature for 10 min to stabilize the luminescence signal.

[0704] c) Read the fluorescence value by the enzyme marker.

[0705] 4. Data processing

[0706] The data was analyzed using GraphPad Prism 8.0 software, and the dose-effect curve was fitted by non-linear S-curve regression, and the IC 50 value was calculated.

[0707] Inhibition rate (Inh%) = 100 - (RLU 化合物RLU 空白 RLU 对照 RLU 空白 * 100%.

[0708] 5. Experimental results

[0709] The compound's inhibitory activity on the proliferation of HER2 775_776insYVMA Ba / F3 cell lines is shown in Table 13. The compound's inhibitory activity on the proliferation of FL-EGFR-WT Ba / F3 cell lines is shown in Table 14.

[0710] Table 13. The compound's inhibitory activity on the proliferation of HER2 775_776insYVMA Ba / F3 cell lines (IC 50 , nM)

[0711] Table 14. The compound's inhibitory activity on the proliferation of FL-EGFR-WT Ba / F3 cell lines (IC 50 , nM)

[0712] As can be seen from Table 13, the compound of the present application has good inhibitory activity on the proliferation of HER2 775-776insYVMA Ba / F3 cell lines (expressing HER2 exon 20 insertion mutation), with an inhibitory IC 50 reaching nanomolar concentration. As can be seen from Table 14, the compound of the present application has weak inhibition on wild-type EGFR, with an inhibitory IC 50 of micromolar concentration. This indicates that the compound of the present application has good selectivity for wild-type EGFR.

[0713] Experimental Example 2: A431 phosphorylation experiment

[0714] Cell culture

[0715] a) All cells were cultured according to the recommended method of ATCC. Cells in the logarithmic growth phase were harvested. Cell viability was detected to ensure that the cell viability was above 90%.

[0716] b) Cell culture medium: DMEM, 10% FBS, 1% Glutamax and 1% P / S. The cell concentration was adjusted, and 40 μL of cell suspension was added to a 384-well plate, centrifuged at 1000 rpm for 30 s, and incubated for 4 hours.

[0717] c) The culture medium was removed, 25 μL of HBSS was added to the 384-well plate, and it was left overnight.

[0718] 3.2 Drug dilution

[0719] a) Drug stock solution: Drug was dissolved in DMSO to make 10 mM DMSO stock solution.

[0720] b) Drug storage: Drug DMSO stock solution was stored in a short-term (up to 3 months) at room temperature in a desiccator. The rest of the drug was stored at -20 °C for a longer period.

[0721] 3.3 Drug addition

[0722] a) All drugs were diluted 3-fold from 10 mM concentration, 10 concentration gradients.

[0723] b) Cells in the 384-well plate with drug addition were incubated at 37 °C, 5% CO2, 95% humidity for 30 min.

[0724] 3.4 Detection

[0725] a) EGF was added as an activator, and stimulation was performed for 15 min.

[0726] b) Cell lysate was prepared according to the manufacturer's protocol and detection was performed.

[0727] c) AlphaScreen was read by Envision.

[0728] 4. Data processing

[0729] Data were analyzed using GraphPad Prism 8.0 software, and the dose-effect curve was fitted by non-linear S-curve regression, and IC 50 values were calculated accordingly.

[0730] Inhibition rate (Inh %) = 100 - (Signal 化合物 - Signal Ave_PC ) / (Signal Ave_VC - Signal Ave_PC )* 100 %.

[0731] Signal Ave_PC : average value of signal of positive control on the whole plate

[0732] Signal Ave_VC : average value of signal of negative control on the whole plate

[0733] 5. Experimental results

[0734] The inhibition of EGFR phosphorylation (pEGFR) of A431 cell line by compounds is shown in Table 15.

[0735] Table 15. Inhibition of EGFR phosphorylation pEGFR (IC 50 nM) of A431 cell line by compounds

[0736] As can be seen from Table 15, the compounds of the present application have weak inhibition on wild-type EGFR and have good selectivity for wild-type EGFR.

[0737] Experimental Example 3: P-gp substrate evaluation experiment

[0738] 1. Test design

[0739] Cell culture

[0740] 1) High glucose DMEM medium containing L-glutamine, 10% fetal bovine serum, 0.1 mg / mL streptomycin and 0.6 μg / mL penicillin were used.

[0741] 2) MDCKII-MDR1 was cultured in T-75 cell culture flasks. The incubator was set at 37°C, 5% CO2, and 95% relative humidity. When the cell confluence reached 70-90%, it could be used for inoculation of Transwell.

[0742] 3) Before cell inoculation, 50 μL of cell culture medium was added to each well of the upper chamber of Transwell, and 25 mL of cell culture medium was added to the lower culture plate.

[0743] After incubation in a 37°C, 5% CO2 incubator for 1 hour, the culture plate could be used for cell inoculation.

[0744] 4) The cells were gently washed with 5 mL of PBS. The PBS was discarded, 1.5 mL of trypsin containing EDTA was added, and the cells were incubated at 37°C for 5 to 10 minutes until they were completely detached. The digestion was terminated by adding serum-containing medium.

[0745] 5) The cell suspension was transferred to a round-bottom centrifuge tube and centrifuged at 120 x g for 10 minutes.

[0746] 6) The cells were resuspended with medium to a final concentration of 1.56 x 10 6 cells / mL.

[0747] MDCKII-MDR1 cell inoculation

[0748] 1) The cell suspension was added to the upper chamber of the 96-well Transwell culture plate at 50 μL per well, with a final inoculation density of 1.45 x 10 5 cells / cm 2 .

[0749] 2) The medium was changed 24 hours after inoculation, and the cells were cultured for 4-8 days, with medium changed every other day.

[0750] Evaluation of cell monolayer membrane integrity

[0751] 1) MDCKII-MDR1 and MDCKII should be fully confluent and differentiated after 4-8 days of culture. At this time, they can be used for penetration assay.

[0752] 2) Measure the resistance of the monolayer membrane with an ohmmeter (Millipore, USA) and record the resistance per well.

[0753] 3) After the end of the assay, place the Transwell plates back in the incubator.

[0754] 4) Calculation of the resistance value:

[0755] Resistance value (ohms) x membrane area (cm 2 ) = TEE value (ohm-cm 2 )

[0756] If the TEE value is < 42 ohms-cm 2 , the well cannot be used for penetration assay.

[0757] Drug penetration assay

[0758] 1) Take the MDCKII-MDR1 Transwell plates out of the incubator. Rinse the cell monolayer membrane twice with HBSS (10 mM HEPES, pH 7.4) buffer and incubate at 37°C for 30 minutes.

[0759] 2) Measure the rate of transport of the compound from apical to basolateral. Add 125 μL of test drug or control drug in HBSS (10 mM HEPES, pH 7.4) buffer to the upper chamber (apical) per well and 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to the lower chamber (basolateral) per well.

[0760] 3) Measure the rate of transport of the compound from basolateral to apical. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to the upper chamber (apical) per well and 75 μL of test drug or control drug in HBSS (10 mM HEPES, pH 7.4) buffer to the lower chamber (basolateral) per well.

[0761] 4) After combining the upper and lower transport devices, incubate at 37°C for 2 hours.

[0762] 5) After incubation, 50 μL from each well of the upper and lower chamber of the Transwell plate was sampled into a new sample tube. Four volumes of acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 200 nM diclofenac, 100 nM tolbutamide) were added to the sample tube, vortexed for 5 minutes and centrifuged at 3,220 g for 15 minutes. 100 μL of the supernatant was diluted with an equal volume of water and analyzed by LC-MS / MS. All samples were prepared in triplicate.

[0763] 6) The integrity of the cell monolayer membrane was evaluated after 2 hours of incubation using a fluorescent dye leakage assay. The fluorescent dye, Lucifer Yellow, was diluted in HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. 100 μL of the Lucifer Yellow solution was added to each well of the upper Transwell insert plate and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of the solution from each well was removed from the upper and lower chamber and added to a new 96-well plate. Fluorescence was measured using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0764] 2. Data processing

[0765] Data calculations were performed using Excel. The apparent permeability coefficient (Papp) of the compounds (unit: cm / s) was calculated using the following equation: app

[0766] The membrane area in the equation is the membrane area of the Transwell-96 well plate (0.143 cm2); the incubation time is in seconds (s). 2

[0767] The efflux ratio was calculated using the following equation:

[0768] 3. Experimental results

[0769] The results of the efflux of the compounds on P-gp substrates are shown in Table 16.

[0770] Table 16. Efflux ratio of the test compounds

[0771] Example 4: Cassette pharmacokinetic testing of the compounds in mice

[0772] ​​Experimental purpose: ICR mice as test objects, LC-MS / MS method is used to detect the drug concentration of the compound in the plasma at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after intragastrical (PO) administration, to study the pharmacokinetic behavior of the compound in mice, and to evaluate its pharmacokinetic characteristics.

[0773] Drug configuration: The compound is dissolved in 10% DMSO+10%Solutol HS15+5%Cremophor EL+20%PEG400+55%(20%Captisol aqueous solution) to form a clear solution for PO administration. The administration method is cassette dosing, and the administration dose of the compound is 10mg / kg. The pharmacokinetic parameter results are shown in Table 17.

[0774] Table 17. Cassette pharmacokinetic parameter results in mice

[0775] As can be seen from Table 17, the compound of the present application has good exposure.

[0776] Experimental example 5: pharmacokinetic test of the compound in mice

[0777] Experimental purpose: ICR male mice (SPF level, source: Beijing Vitoohua Experimental Animal Technology Co., Ltd.) as test objects, 3 per group, single intragastrical (PO) administration of the compound, LC-MS / MS method is used to detect the drug concentration of the compound in the plasma at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, to study the pharmacokinetic behavior of the compound in mice, and to evaluate its pharmacokinetic characteristics.

[0778] Drug configuration: The compound is dissolved in 10% DMSO+10%Solutol HS15+5%Cremophor EL+20%PEG400+55%(20%Captisol aqueous solution) to form a clear solution for PO administration. The administration method is single intragastrical, and the animals are fasted overnight (10-14 hours) before administration. The administration dose of the compound is 10mg / kg. The pharmacokinetic parameters are calculated by Phoenix WinNonlin8.2.0 using blood drug concentration data at different time points, and the results are shown in Table 18.

[0779] Table 18. Pharmacokinetic parameter results in mice

[0780] As can be seen from Table 18, the compound of the present application has good exposure.

[0781] Experimental Example 6: In Vivo Pharmacodynamic Study of the Test Substance on a Subcutaneous Syngeneic Transplant Tumor Nude Mouse Model of Ba / F3-HER22 A775-G776insYVMA Cells

[0782] 1. Experimental Purpose

[0783] Evaluate the in vivo pharmacodynamics of the compound of the present invention on a subcutaneous syngeneic transplantation tumor model of Ba / F3-HER2 A775-G776insYVMA cells.

[0784] 2. Experimental Animals

[0785] 2.1 Animal Source

[0786] Balb / c nude mice, female, 6 - 8 weeks old, weighing 18 - 22 g, a total of 30 mice, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., production license number: SCXK(Beijing)2021 - 0011.

[0787] 2.2 Animal Rearing

[0788] After the animals arrive, they are quarantined and reared in the experimental environment for 3 - 7 days before the experiment can begin. The animals are reared in an SPF-class animal room with individually ventilated cages, no more than 5 animals per cage. Temperature: 20 - 26°C. Humidity: 35 - 75%. Lighting: 12 hours of illumination and 12 hours of darkness. Litter: Corn cob litter, changed once a week. Feed: Irradiated mouse and rat feed, purchased from Wuhan Wanqian Jiaxing Biotechnology Co., Ltd., free access to food. Diet: Free access to food, dry pellet feed is sterilized by radiation. Drinking water: Free access to drinking water, drinking water is acidified and sterilized. Animal marking: Ear tags, each cage is hung with an experimental information label card, including mouse information, cell inoculation information, animal experiment information, etc.

[0789] 3. Experimental Materials

[0790] 3.1 Cell Construction

[0791] Through a retroviral packaging system, the HER2 A775-G776insYVMA gene was transferred into wild-type cells Ba / F3 (RIKEN BRC CELL BANK, Resource NO: RCB0805, Lot NO: 11). After one round of screening with puromycin antibiotic and continued culturing of the cells in a medium without interleukin-3, the stable transfection cell line Ba / F3-HER2 A775-G776insYVMA was obtained.

[0792] 3.2 Cell Culture

[0793] Ba / F3-HER2 A775-G776insYVMA cell line was cultured in 1640 medium + 10% FBS, 37℃ 5% CO2, and subcultured 2-3 times a week. When the cell saturation was 80%-90% and the number reached the required amount, the cells were collected, counted, and inoculated.

[0794] 3.3 Culture medium and Matrigel

[0795] 1640 basal medium and fetal bovine serum (FBS) were purchased from Viva cell company. Matrigel was purchased from ABW standard type containing phenol red, item number: 082704, volume 1:1.

[0796] 3.4 Solvent prescription and storage conditions of drug solution

[0797] Drug preparation frequency: once every 3 days; ensure sufficient dissolution / vortexing before administration, administration volume: 10 μL / g.

[0798] Solvent: 10% DMSO + 40% PEG400 + 50% PG solution; final product 10, 34, 45 were prepared into 5 mg / mL with 10% DMSO + 40% PEG400 + 50% PG solution.

[0799] 4. Experimental design

[0800] Cell line: Ba / F3-HER2 A775-G776insYVMA, see Tables 19, 20, and 21 for administration scheme.

[0801] Table 19. Grouping and administration scheme of the test compound (final product 10) for efficacy experiment

[0802] Table 20. Grouping and administration scheme of the test compound (final product 34) for efficacy experiment

[0803] Table 21. Grouping and administration scheme of the test compound (final product 45) for efficacy experiment

[0804] 5. Test method

[0805] 5.1 Model establishment

[0806] 0.2 mL (1 × 10 6 Ba / F3-HER2 A775-G776insYVMA cells (with Matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached about 100-120 mm 3Grouping begins on the day of dosing. The SEM value of each group is less than 10% of the average value of each group. The day of grouping is recorded as Day 0, and dosing begins according to the body weight of the animals. During the dosing period, if the body weight of an individual animal decreases by more than 15% (BWL≥15%) compared with Day 0, the animal will be removed from the experiment and dosing will be stopped until the body weight of the animal recovers (BWL<15%) and dosing is resumed.

[0807] 5.2 Weighing and observation

[0808] Body weight and tumor volume are measured twice a week. Tumor length and width are measured using a digital caliper, and tumor volume is estimated based on the length and width measurements.

[0809] Clinical symptoms of the animals are observed and recorded once a day during the experiment. Clinical observations include the overall health of the animals, abnormal body weight, abnormal behavior, and other drug-related adverse reactions.

[0810] 5.3 Explanation of experimental endpoints

[0811] According to the relevant regulations on animal welfare, if an individual experimental animal meets any of the following conditions during the experiment, the animal will be removed from the experimental group and euthanized. 1. The body weight of the animal decreases by more than 20% (BWL≥20%) compared with Day 0; 2. The animal exhibits severe adverse reactions such as blindness, paralysis, etc.; 3. The tumor volume is greater than 2000mm 3 ; 4. Open ulcers form on the surface of the tumor. The method of euthanizing the animals is to confirm the death of the animals after CO2 anesthesia. After the end of the experiment, the remaining animals are euthanized and killed with CO2, the tumor is weighed, and photographs are taken for record.

[0812] 5.4 Evaluation indicators

[0813] The formula for calculating the tumor volume (Tumor Volume, TV) is: 1 / 2×a×b 2 , where a and b are the length and width of the tumor measurements, respectively.

[0814] The formula for calculating the tumor growth inhibition rate (%TGI TV ) is: TGI (%) = [(1-(the average tumor volume at the end of dosing in a certain treatment group - the average tumor volume at the start of dosing in that treatment group)) / (the average tumor volume at the end of treatment in the solvent control group - the average tumor volume at the start of treatment in the solvent control group)]×100%.

[0815] The formula for calculating the relative tumor volume (Relative Tumor Volume, RTV) is: Vt / V0, where V0 is the tumor volume at the time of grouping and Vt is the tumor volume at each measurement.

[0816] The formula for calculating the relative tumor growth rate (%T / C RTV) The calculation formula is: T / C% = TRTV / CRTV x 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). According to the results of tumor measurement, the relative tumor volume (RTV) is calculated, and the calculation formula is RTV = Vt / V0, wherein V0 is the average tumor volume measured at the time of grouping (i.e. DO), and Vt is the average tumor volume at a certain time after treatment, and TRTV and CRTV take the same day data.

[0817] The calculation formula of the animal weight change rate (%BWC) is: (BWC t - BW0) / BW0 x 100%, wherein BW t is the animal weight at each measurement, and BW0 is the animal weight at the time of grouping.

[0818] The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. The antitumor effect of the compound is evaluated by using the relative tumor proliferation rate T / C (%) as the experimental evaluation index. In principle, the evaluation criteria are: T / C (%) > 40% is invalid; T / C (%) ≤ 40%, and p < 0.05 is significantly different.

[0819] 6. Statistical analysis

[0820] In this study, the experimental data are expressed as Mean ± SEM.

[0821] The tumor growth curve is plotted with the time point as the X axis and the tumor volume (mm 3 ) as the Y axis; and the animal weight change curve is plotted with the time point as the X axis and the animal weight (g) as the Y axis. The single factor variance analysis ANOVA is used for comparison between groups, and if the variance is not uniform, the non-parametric test Mann-Whitney test is selected for analysis, P < 0.05 is a significant difference, and P < 0.01 is a very significant difference (IBM SPSS Statistics 19.0).

[0822] 7. Results

[0823] The experimental results are shown in Figures 1-6. As can be seen from Figures 1, 3 and 5, compared with the solvent control group, the compounds of the present application show obvious antitumor effect. Moreover, the tumor-bearing mice in each treatment group show good tolerance to the compounds of the present application, and there is no obvious weight loss, as shown in Figures 2, 4 and 6.

[0824] The above examples are only used to help understand the method of the present application and its core idea. It should be pointed out that for ordinary skilled persons in the technical field, some improvements and modifications can be made to the present application without departing from the principles of the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

A fused ring compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate, or solvate thereof: wherein, In formula I, represents a single bond or a double bond; X 1 , X 2 each independently N or C, and X 1 , X 2 are not simultaneously N; X 3 is N, C or CR 4 ; X 4 is N, CR 5 , O or S; X 5 is N, C or CR 6 ; X 6 For chemical bonds, N or CR 7 ;X 1 X 2 X 3 X 4 X 5 X 6 There can be at most 3 N values ​​simultaneously, and X 1 X 2 X 3 X 4 X 5 X 6 Two adjacent chemical bonds connecting two objects cannot both be double bonds; L is absent, O, N(R 8 ), C(R 9 )=C(R 10 ), C(=O), S, S(=O), or S(=O)2; L1is absent, O, N(R 8 ), C(R 9 )2, -OR 10 ), -NR 11 ), -C(=O), -S, -S(=O) or -S(=O)2; and 11 L2is absent, O, N(R 8 ), C(R 9 )2, -OR 10 ), -NR 11 ), -C(=O), -S, -S(=O) or -S(=O)2; and 11 L2is absent or is N(R 12 ) or CH2OH; Y is N or CR 13 ; A is absent or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 3- to 12-membered cycloalkyl-C 14 R 15 , OR 16 , SR 16 , 3- to 12-membered cycloalkyl-C 1-6 alkylene-, 3- to 12-membered heterocyclyl-C 1-6 alkylene-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl comprising 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 3- to 12-membered cycloalkyl-C 1-6 alkylene-, 3- to 12-membered heterocyclyl-C 1-6 alkylene- optionally substituted with one or more R'; Z is C=0 or S(=0)2; E is a 6-10 membered aryl group, a 5-10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, the 6-10 membered aryl group, the 5-10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S being optionally substituted by one or more R'; G is 6-12 membered aryl, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-10 membered heteroaryl N-oxide containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 6-12 membered aryl-C 1-6 alkylene-, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-10 membered heteroaryl N-oxide containing at least 1 N atom containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-10 membered heteroaryl N-oxide containing at least 1 N atom containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene-, 5-10 membered heteroaryl N-oxide containing at least 1 N atom containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene- is optionally substituted by one or more R'; R 1 is dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylenyloxy or C 4-6 cycloalkenyl, said dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylenyloxy or C 4-6 cycloalkenyl is optionally substituted by one or more halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, deuterium atom, 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 6-12 membered aryl, C 1-3 alkoxy-C 1-3 alkylene- or NR x R y substituted, said C 1-4 alkyl, halogenated C 1-4 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, 5-12 membered heteroaryl containing 1 or more heteroatoms selected from N, O, S, 6-12 membered aryl or C 1-3 alkoxy-C 1-3 alkylene- optionally substituted by one or more R'; R 2 , R 3 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, a 3-12 membered heterocyclyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, said C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, a 3-12 membered heterocyclyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, optionally substituted with one or more R'; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3-12 membered cycloalkyl group, a C 1-6 alkoxy group, an amino group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a 3-12 membered heterocyclyl group having 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), S(O)2, an oxo (=O), the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the 3-12 membered cycloalkyl group, the C 1-6 alkoxy group, the amino group, the C 1-6 alkylamino group, the di(C 1-6 alkyl)amino group, the 3-12 membered heterocyclyl group is optionally substituted with one or more R'; R 11 C 1-6 alkylene, said C 1-6 alkylene is optionally substituted with one or more R'. or R 3 with the atom to which they are attached, form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, a 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, a 6-12 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 6-12 membered aryl being optionally substituted by one or more R'; or 7 with the atom to which they are attached, form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, a 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, a 6-12 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms or, when X 6 is a chemical bond, R 3 and the C atom to which it is attached form, together with L 1 , a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, a 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, a 6-12 membered aryl, which 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, 5-12 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 6-12 membered aryl is optionally substituted by one or more R'; or R 9 with the carbon atom to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3-12 membered cycloalkyl, 3-12 membered heterocyclyl being optionally substituted by one or more R'; or 10 with the carbon atom to which they are attached form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3-12 membered cycloalkyl, 3-12 membered heterocyclyl being optionally substituted by one or more R'; or R 14 , R 15 , R 16 each independently is a hydrogen atom, C 1-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, 3- to 12-membered cycloalkyl-C 1-6 alkylene-, 3- to 12-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2-C 1-6 alkylene-, said C 1-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, 3- to 12-membered cycloalkyl-C 1-6 alkylene-, 3- to 12-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2-C 1-6 alkylene- is optionally substituted with one or more R'; Or, R 14 With R 15 Together with the N atoms they are connected to, they form a 3-12 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2, wherein the 3-12 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O), S(=O)2 is optionally substituted by one or more R′. R' is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a cyano group, a nitro group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group having one or more heteroatoms each independently selected from N, O, S, S(=0), S(=0)2, a halo-C 1-6 alkyl group, a halo-C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkyl group, a hydroxy-C 1-6 alkyl group, an amino-C 1-6 alkyl group, a cyano-C 1-6 alkyl group, OR e , SR e , S(=0)R e , S(=0)2R e , C(=0)R e , C(=0)NR e , C(=0)OR e , NR e R f , NR e C(=0)R f , OC(=0)R e , S(=0)NR f , S(=0)2NR e , NHS(=0)2R e , NHS(=0)R e , NR e C(=0)OR f , NR e C(=0)NR f , -(0)(=0R e )2, P(=0)(R e )2, or oxo (=0), said C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group having one or more heteroatoms each independently selected from N, O, S, S(=0), S(=0)2, a halo-C 1-6 alkyl group, a halo-C 1-6 alkoxy group, a hydroxy-C 1-6 alkyl group, an amino-C 1-6 alkyl group, a cyano-C 1-6 alkyl group is optionally substituted with one or more R"; R" are each independently a deuterium atom, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, deuteratedC 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, S(=0), S(=0)2, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, haloC 1-6 alkoxy or oxo (=0); R a , R b , R c each independently is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkylene-, C 1-6 alkylamino-C 1-4 alkylene-, di(C 1-6 alkyl)amino-C 1-4 alkylene-, 3-7 membered cycloalkyl-C 1-4 alkylene-, 3-12 membered heterocyclyl-C 1-4 alkylene-, 3-12 membered heterocyclyl, halo-C 1-6 alkyl, 3-7 membered cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkylene-, C 1-6 alkylamino-C 1-4 alkylene-, di(C 1-6 alkyl)amino-C 1-4 alkylene-, 3-7 membered cycloalkyl-C 1-4 alkylene-, 3-12 membered heterocyclyl-C 1-4 alkylene-, 3-12 membered heterocyclyl, halo-C 1-6 alkyl, 3-7 membered cycloalkyl optionally substituted by one or more R'; R e , R f each independently is a hydrogen atom, a deuterium atom, a C 1-4 alkyl group, a haloC 1-4 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered heterocyclyl group having one or more heteroatoms selected from the group consisting of N, O, S, S=O, S(O)2; or R e and R f together with the connecting N atom form a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S=0, S(0)2; R x , R y each independently is a hydrogen atom, a C 1-4 alkyl group, a halo-C 1-4 alkyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group with one or more heteroatoms selected from N, O, S, S(=O), S(=O)2, a 3- to 12-membered cycloalkyl-C 1-4 alkylene group, a 3- to 12-membered heterocyclyl-C 1-4 alkylene group, a C 1-4 alkoxy-C 1-4 alkylene group, or a deuterated C 1-4 alkyl group, the C 1-4 alkyl group, a halo-C 1-4 alkyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group with one or more heteroatoms selected from N, O, S, S(=O), S(=O)2, a 3- to 12-membered cycloalkyl-C 1-4 alkylene group, a 3- to 12-membered heterocyclyl-C 1-4 alkylene group, a C 1-4 alkoxy-C 1-4 alkylene group, or a deuterated C 1-4 alkyl group optionally substituted with one or more R'; or R x with the attached N atom form a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, which 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2 is optionally substituted with one or more R'. y with the attached N atom form a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, which 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2 is optionally substituted with one or more R'. The fused ring compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate, or solvate thereof, having the structure of Formula II, III, or IV: wherein, R 20 , R 30 , R 40 , R 50 each independently R'; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y, L, L1, L2, A, Z, G, R 1 , R 2 , R 3 , R' is as defined in claim 1. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to claim 1 or 2, wherein, In formula I, II, III, or IV, X 1 , X 2 each independently is C; Preferably, in formula I, II, III or IV, X 3 is N, C or CR 4 ; More preferably, X 3 is N or C; Preferably, in formula I, II, III or IV, X 4 is N or CR 5 ; Preferably, in formula I, II, III or IV, X 5 is N, C or CR 6 ; More preferably, X 5 is N or C; Most preferably, X is C; 5 is C;​ Preferably, in formula I, II, III or IV, X 6 is a chemical bond, N or CR 7 ; More preferably, X 6 is a chemical bond or CR 7 ; Preferably, X 3 X 4 X 5 X 6 There can be at most 3 N values ​​simultaneously, and X 1 X 2 X 3 X 4 X 5 X 6 Two adjacent chemical bonds connecting two objects cannot both be double bonds; Preferably, in formula I, II, III or IV, L is absent or O, N(R 8 ) or C(R 9 R 10 ). More preferably, L is absent or is O or C(R 9 R 10 ) ; Further preferably, L is O or C(R 9 R 10 ); Preferably, in formulas I, II, III, or IV, L1 is absent or is O or N(R) 8 ), C(R 9 R 10 -OR 11 -or-NR 11 -; More preferably, L1is absent or is O, N(R 8 ), -OR 11 - or -NR 11 -; Most preferably, L1is absent or is O, N(R 8 ); Preferably, in formula I, II, III or IV, L2is absent or N(R 12 ); Preferably, in formula I, II, III or IV, Y is N or CR 13 ; Preferably, in formula I, II, III or IV, Y is N. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 3, wherein, In formula I, II, III or IV, A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-6 alkylene- is optionally substituted by one or more R'; Preferably, A is absent or is methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, azetidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-l,7-diazaspiro[4.5]dec-l-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopenta[C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinylmethyl, tetrahydropyrrolylmethyl, acridinylmethyl, morpholinylmethyl, piperidinylethyl, tetrahydropyrrolylethyl, acridinylethyl, morpholinoethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, the methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, azetidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-l,7-diazaspiro[4.5]dec-l-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopenta[C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinylmethyl, tetrahydropyrrolylmethyl, acridinylmethyl, morpholinylmethyl, piperidinylethyl, tetrahydropyrrolylethyl, acridinylethyl, morpholinoethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, are optionally substituted with one or more of the following: halo, hydroxy, oxo, cyano, nitro, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminoc1] heptane is optionally substituted with one or more F, CI, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino, or oxo (=0);. More preferably, A is absent or selected from the following groups: the above-mentioned groups are optionally substituted by one or more F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino or oxo (=0). The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate, or solvate thereof according to any one of claims 1 to 4, wherein, In formula I, II, III or IV, Z is C=0 or S(=0)2; Preferably, Z is C=0; Preferably, in formula I, E ring is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, C 2-4 alkynyl is optionally substituted with 1, 2, 3 or 4 R'; More preferably, in formula I, E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole, the phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene or pyrazole being optionally substituted by 1, 2, 3 or 4 R'. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 5, wherein, G is phenyl, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene- optionally substituted by one or more R'; Preferably, in formula I, II, III or IV: G is phenyl, pyridyl, phenylmethyl, pyridylmethyl, said phenyl, pyridyl, phenylmethyl, pyridylmethyl, optionally substituted by 1, 2, 3 or 4 deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; represents a single bond or a double bond; B ring is pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; X a , X b , X c are each independently N or CH; X 1a is a bond, N, CH, CH2, S, O, S(O), or S(O)2; X 2a is N, CH, CH2, O, S, S(O) or S(O)2; X 3a , X 4a each independently is N or C, and X 3a and X 4a are not simultaneously N, X 1a , X 2a and X 3a are not simultaneously N; X 5a is a chemical bond, N, CH, CH2, O or S; X 6a is N, O, S or CH; n is 0, 1 or 2; More preferably, in formula I, II, III or IV, G is phenyl, pyridyl, phenylmethyl, pyridylmethyl or is selected from the group consisting of: the above-mentioned groups are optionally substituted by 1, 2, 3 or 4 deuterium atoms, F, Cl, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy; ​ Further preferred, in formula I, II, III, IV, G is selected from the following groups: The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 6, wherein, In formula I, II, III, or IV, R 1 is dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide, or C 4-6 cycloalkenyl, said dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylene oxide, or C 4-6 cycloalkenyl is optionally substituted by one or more halogen, deuterium atom, C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl, or NR x R y is substituted, said C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl is optionally substituted by one or more R'; R x , R y each independently is a hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene- optionally substituted with one or more R'; Or, R x With R y Together with the attached N atom, it forms a 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, S(=O), and S(=O)2, wherein the 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, and S is optionally replaced by one or more R′. R is preferably H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, deuterium, phenyl, pyridinyl, or NR 1 is F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, deuterium, phenyl, pyridinyl, or NR x R is preferably H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, deuterium, phenyl, pyridinyl, or NR y is F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, deuterium, phenyl, pyridinyl, or NR R x , R y each independently is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group, or an azetidinylethyl group, which methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, adamantyl group, methoxyethyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopropylethyl group, cyclobutylethyl group, azetidinylmethyl group, or azetidinylethyl group is optionally substituted with one or more R'; or R x or R y and the attached N atom together form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl being optionally substituted by one or more R'; More preferably, in formula I, II, III or IV, R 1 is selected from the following groups: The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 7, wherein, In formula I, II, III, or IV: R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; Preferably, in formula I, II, III or IV, R 2 is a hydrogen atom; R 3 is selected from a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group; Preferably, R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 Each can be independently a hydrogen atom, deuterium atom, halogen, cyano, methyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, aminomethyl, aminoethyl, or oxo (=O); Preferably, R 11 is methylene, ethylene, propylene; Preferably, R 13 is a hydrogen atom, halogen, cyano. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 8, wherein, R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), said methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, CI, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 9, wherein, in formula I, II, III, or IV, represents a single or double bond; X 1 , X 2 each independently C; X 3 is N, C or CR 4 ; X 4 is N or CR 5 ; X 5 is N, C or CR 6 ; X 6 is a bond, N or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 are simultaneously N, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 the 2 adjacent bonds connected between X and X cannot be simultaneously double bonds; L is absent, O, N(R 8 ) or C(R 9 )2; R 10 ); L1 does not exist or is 0 or N(R) 8 ), C(R 9 R 10 -OR 11 -or-NR 11 -; L2is absent or is N(R 12 ) ; Y is N or CR 13 ; A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene- optionally substituted by one or more R'; Z is C=0 or S(=0)2; E ring is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, S being optionally substituted with 1, 2, 3, or 4 R'; G is phenyl, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom, phenyl-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene-, 6-12 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene-, 6 membered heteroaryl N-oxide containing at least 1 N heteroatom-C 1-2 alkylene- is optionally substituted by one or more R'; R 1 is dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylenyloxy, or C 4-6 cycloalkenyl, said dihalogenomethyl, C 2-4 alkenyl, C 2-4 alkynyl, propylenyloxy, or C 4-6 cycloalkenyl is optionally substituted by one or more halogen, deuterium atom, C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl, or NR x R y substituted, said C 1-4 alkyl, C 1-3 alkoxy-C 1-3 alkylene-, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms selected from N, O, S, 5-6 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms selected from N, O, S, phenyl is optionally substituted by one or more R'; R x , R y each independently is a hydrogen atom, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene-, said C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-6 membered heterocyclyl containing 1 or more heteroatoms selected from N, O, S-C 1-4 alkylene- or C 1-4 alkoxy-C 1-4 alkylene- optionally substituted with one or more R'; or R x with the attached N atom form a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S is optionally substituted with one or more R'; or y with the attached N atom form a 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S, S(=0), S(=0)2, said 3-12 membered heterocyclyl containing one or more heteroatoms selected from N, O, S is optionally substituted with one or more R'; R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group; R 11 is methylene, ethylene, propylene; R 13 is a hydrogen atom, halogen, cyano; R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, dimethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), said methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted by one or more deuterium atoms, F, CI, hydroxyl, methyl, ethyl, isopropyl, or cyclopropyl; Preferably, in formula I, II, III or IV, represents a single or double bond; X 1 , X 2 each independently C; X 3 is N, C or CR 4 ; X 4 is N or CR 5 ; X 5 is N, C or CR 6 ; X 6 For chemical bonds, N or CR 7 ;X 3 X 4 X 5 X 6 There can be at most 3 N values ​​simultaneously, and X 1 X 2 X 3 X 4 X 5 X 6 Two adjacent chemical bonds connecting two objects cannot both be double bonds; L is absent, O, N(R 8 ) or C(R 9 )2; R 10 ); L1is absent, O, N(R 8 ), C(R 9 )2, S, S(O)2, SO2N(R 10 ), N(R 11 )SO2, or N(R 11 ); L2is absent, O, N(R 8 ), C(R 9 )2, S, S(O)2, SO2N(R L2is absent or is N(R 12 ) ; Y is N or CR 13 ; A is absent or C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, 3-6 membered cycloalkyl-C 1-4 alkylene-, 4-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S-C 1-4 alkylene- optionally substituted by one or more R'; Z is C=0; E ring is phenyl, 5-6 membered heteroaryl containing 1, 2, 3, 4 heteroatoms selected from N, O, S, said phenyl, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S being optionally substituted by 1, 2, 3 or 4 R'; G is phenyl, pyridyl, phenylmethyl, pyridylmethyl, said phenyl, pyridyl, phenylmethyl, pyridylmethyl, optionally substituted by 1, 2, 3 or 4 deuterium atoms, F, CI, cyano, hydroxyl, amino, methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy; B ring is pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine or triazine; X a , X b , X c each independently N or CH; X 1a is a chemical bond, N, CH, CH2, S, O, S(O), or S(O)2; X 2a is N, CH, CH2, O, S, S(O) or S(O)2; X 3a , X 4a each independently N or C, and X 3a and X 4a are not simultaneously N, X 1a , X 2a and X 3a are not simultaneously N; X 5a is a chemical bond, N, CH, CH2, O or S; X 6a is N, O, S or CH; n is 0, 1 or 2; R 1 is dihalomethyl, ethenyl, propenyl, ethynyl, propynyl, butynyl, propylenoxy, butylenoxy, cyclopentenyl or cyclohexenyl, which is optionally substituted by one or more F, Cl, methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxy, butylenoxy, deuterium, phenyl, pyridyl or NR x R y substituted, which methyl, ethyl, propyl, isopropyl, methoxymethyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, propylenoxy, butylenoxy, phenyl, pyridyl is optionally substituted by one or more R'; R x , R y each independently is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an adamantyl group, a methoxyethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, an azetidinylmethyl group, or an azetidinylethyl group, which methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, adamantyl group, methoxyethyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopropylethyl group, cyclobutylethyl group, azetidinylmethyl group, or azetidinylethyl group is optionally substituted with one or more R'; or R x or R y and the attached N atom together form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, 7-azabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-oxa-5-azaspiro[3.5]nonanyl, tetrahydro-1H,3H-5-furo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl being optionally substituted by one or more R'; R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group; R 11 is methylene, ethylene, propylene; R 13 is a hydrogen atom, halogen, cyano; R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), said methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, CI, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl; More preferably, in formula II, II, III, or IV: represents a single or double bond; X 1 , X 2 each independently C; X 3 is N or C; X 4 is N or CR 5 ; X 5 is N or C; X 6 is a bond or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 the 2 adjacent bonds connected to X cannot both be double bonds; L is absent, O, or C(R 9 R 10 ); L1is absent, O, N(R 8 ), -OR 11 -, or -NR 11 ; L2is absent or is N(R 12 ); Y is N or CR 13 ; A is absent or methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, azetidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-l,7-diazaspiro[4.5]dec-l-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopenta[C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinylmethyl, tetrahydropyrrolylmethyl, acridinylmethyl, morpholinylmethyl, piperidinylethyl, tetrahydropyrrolylethyl, acridinylethyl, morpholinoethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, the methyl, ethyl, propyl, piperidinyl, tetrahydropyrrolyl, azetidinyl, piperazinyl, morpholinyl, azepanyl, tetrahydropyridinyl, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, cyclobutyl, cyclopentyl, cyclohexyl, 2,6-diazaspiro[3.3]heptane, 3-oxa-l,7-diazaspiro[4.5]dec-l-ene, 4,5-dihydrooxazole, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 2,6-diazaspiro[3.3]heptane, octahydrocyclopenta[C]pyrrole, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 6-azabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,8-diazaspiro[4.5]decane, 2-azabicyclo[3.1.0]hexane, piperidinylmethyl, tetrahydropyrrolylmethyl, acridinylmethyl, morpholinylmethyl, piperidinylethyl, tetrahydropyrrolylethyl, acridinylethyl, morpholinoethyl, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, are optionally substituted with one or more of the following: halo, hydroxy, cyano, oxo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkylthio, C1-C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C6alkoxycarbonyl, C1-C6haloalkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6haloalkylcarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6halodialkylaminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6haloalkylaminocarbonyl, C1-C6dialkylaminocarb1] heptane is optionally substituted with one or more F, CI, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino, or oxo (=0);. Z is C=0; E is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene, or pyrazole, said phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, thiophene, or pyrazole being optionally substituted with 1, 2, 3, or 4 R'; G is phenyl, pyridyl, phenylmethyl, pyridylmethyl or is selected from the group consisting of: said phenyl, pyridyl methyl, pyridylmethyl, or the above groups being optionally substituted with 1, 2, 3, or 4 deuterium atoms, F, CI, cyano, hydroxy, amino, methyl, ethyl, isopropyl, deuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methylamino, dimethylamino, formyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy; More preferably, in formula II, II, III, or IV: R 1 selected from the group consisting of: R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; R 5 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group; R 11 is methylene, ethylene, propylene; R 13 is a hydrogen atom, halogen, cyano; R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, dimethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), which methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 is optionally substituted with one or more deuterium atoms, F, CI, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl; Further preferred, in formula I, II, III, or IV: represents a single or double bond; X 1 , X 2 each independently C; X 3 is N or C; X 4 is N or CR 5 ; X 5 is N or C; X 6 is a chemical bond or CR 7 ; X 3 , X 4 , X 5 , X 6 up to 3 of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 the 2 adjacent connected X's cannot both be double bonds; L is O or C(R 9 R 10 ); L1 does not exist or is 0 or N(R) 8 -OR 11 -or-NR 11 -; L2is absent or is N(R 12 ) ; Y is N or CR 13 ; A is absent or selected from the following groups: the above-mentioned groups are optionally substituted with one or more F, CI, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethynyl, cyano, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, amino, methylamino, dimethylamino, or oxo (=0); Z is C=0; E ring is phenyl, pyridyl, pyrimidine, pyridazine, pyrazine, which phenyl, pyridyl, pyrimidine, pyridazine, pyrazine is optionally substituted with 1, 2, 3, or 4 R'; G is selected from the following groups: R 1 selected from the group consisting of: R 2 , R 3 each independently is a hydrogen atom, an amino group, a deuterium atom, a halogen, a cyano group, a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; R 5 , R 7 , R 8 , R 9 , R 10 , R 12 each independently is a hydrogen atom, a deuterium atom, a halogen, a cyano group, a methyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, a trifluoroethyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, a methoxymethyl group, an ethoxymethyl group, an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, an aminoethyl group, or an oxo (=0) group; R 11 is methylene, ethylene, propylene; R 13 is cyano; R' is a hydrogen atom, a deuterium atom, F, CI, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2, or oxo (=0), said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, methylamino, ethylamino, methoxymethyl, methoxyethyl, methylaminoethyl, dimethylaminoethyl, S(=0)CH3, S(=0)2CH3, C(=0)CH3, C(=0)NCH3, NHC(=0)CH3, S(=0)2NCH3, P(=0)(CH3)2, or P(=0)(CH2CH3)2 being optionally substituted with one or more deuterium atoms, F, CI, hydroxy, methyl, ethyl, isopropyl, or cyclopropyl. The fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, or solvate thereof according to any one of claims 1 to 10, wherein, The compounds of formula I, II, III, IV are selected from the group consisting of the following compounds: A pharmaceutical composition comprising the fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof of any one of claims 1-11, and a pharmaceutically acceptable carrier or excipient; Preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, spray. Use of the fused ring compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof of any one of claims 1-11 and / or the pharmaceutical composition of claim 12 in the manufacture of a medicament for the treatment of a disease mediated by HER2 abnormality. Preferably, the disease is a neoplastic disease. More preferably, the oncological 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, non-small cell lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma, atherosclerosis, or pulmonary fibrosis. A method of treating a disease mediated by HER2 abnormality, the method comprising administering to a patient in need thereof a therapeutically effective amount of the fused ring compound of any one of claims 1-11 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopically-labeled, deuterated, N-oxide, prodrug molecule, hydrate or solvate thereof and / or the pharmaceutical composition of claim 12; Preferably, the disease is a neoplastic disease; More preferably, the oncological 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, non-small cell lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

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