Amino heteroaryl macrocyclic compound as well as preparation method and application thereof

Abstract

The invention relates to an amino heteroaryl macrocyclic compound as well as a preparation method and application thereof, the structure of the amino-containing heteroaryl macrocyclic compound is as shown in formula I: # imgabs0 #, and the definitions of A, M, E, X1, X2, L2, R1, R2, R3, R4, m, n and t are as described in the specification. The amino heteroaryl macrocyclic compound has a high-efficiency and high-selectivity inhibition effect on an epidermal growth factor receptor (EGFR), and can be used for treating related diseases caused by abnormal induction of the EGFR, especially treating cancer diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug preparation, and specifically relates to aminoheteroaryl macrocyclic compounds and pharmaceutical compositions thereof, and also relates to the use of such compounds and pharmaceutical compositions thereof in treating protein kinase-mediated diseases such as cancer. Background Art

[0002] Protein kinases are enzymatic components of signal transduction pathways that catalyze the migration of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and / or threonine residues of proteins. Therefore, compounds that inhibit protein kinase function (i.e., protein kinase inhibitors) are valuable tools for evaluating the physiological consequences of protein kinase activity. Although protein kinase inhibitors have achieved great success in targeted cancer therapy, secondary mutations in the kinase domain can occur during treatment, resulting in drug resistance. Therefore, there is an unmet clinical need for protein kinase inhibitors that can act on both primary driver gene mutations and secondary resistance mutations.

[0003] EGFR is a member of the ErbB receptor family of receptor tyrosine kinases. When EGFR binds to its ligand outside the cell, the receptor undergoes homotypic or heterotypic dimerization and autophosphorylation, activating downstream cascade signaling pathways, ultimately promoting cell growth, proliferation, and division. Overexpression (upregulation) or overactivity (amplification or mutation) of EGFR has been shown to be associated with many cancers, including head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colorectal cancer, non-small cell lung cancer, and glioblastoma.

[0004] EGFR, as an oncogene, has generated targeted therapy for EGFR small molecule inhibitors. In non-small cell lung cancer (NSCLC), 50%-80% of patients are caused by EGFR mutations (mainly in-frame deletion mutations Ex19Del in exon 19 and lysine replaced by arginine at position 858 in exon 21 L858R, both of which are also called EGFR sensitive mutations). Currently, three generations of EGFR small molecule inhibitors have been approved for the treatment of patients with EGFR mutation non-small cell lung cancer. The first and second generation EGFR inhibitors such as Iressa, Tarceva, afatinib, dacomitinib, etc. have achieved great success in the treatment of NSCLC. However, there are very obvious side effects such as rash and diarrhea in the clinic, and after one year of use, patients develop drug resistance. Clinical data show that about 50% of patients have acquired resistance due to the T790M (threonine replaced by methionine at position 790 in exon 20) mutant.

[0005] The third-generation EGFR inhibitors such as osimertinib are irreversible inhibitors that can covalently bind to C797 to greatly improve its activity. They can be used as second-line treatment for patients with EGFR T790M mutations after treatment with first- and second-generation EGFR inhibitors, and can also be used as first-line treatment for patients with EGFR sensitive mutations. However, osimertinib as a second-line treatment for patients with EGFR T790M mutations will inevitably produce C797X triple resistance mutations (cysteine ​​at position 797 of exon 20 mutates to serine or glycine, etc.) after 9.9-10.1 months of treatment.

[0006] Thress KS first reported that 40% of patients with T790M mutation who took osimertinib developed C797S triple resistance mutation. In addition, Lee JY et al. also reported that 24% of patients with T790M mutation would develop C797S triple resistance mutation after taking osimertinib. Papadimitrakopoulou VA analyzed 73 patients with disease progression who took osimertinib in the AURA3 clinical trial and found that 15% of patients developed C797S triple resistance mutation.

[0007] Osimertinib showed good efficacy as first-line treatment compared with standard treatment with first-generation EGFR inhibitors (gefitinib or erlotinib), with a PFS of 18.9 months vs 10.2 months. A study of 91 patients with osimertinib-resistant disease in the FLAURA study found that 7% of patients had C797S dual resistance mutations.

[0008] For patients with EGFR sensitive mutations, the best recommended first-line treatment is the use of third-generation EGFR inhibitors such as osimertinib. Therefore, after using osimertinib for a period of time, C797X dual resistance mutations are inevitable. Currently, there is no drug approved to treat patients with C797X mutations, and there is an unmet clinical need.

[0009] In addition to the common sensitive mutations Ex19Del and L858R, about 4-10% of lung cancer patients have EGFR exon 20 insertion mutations, most of which occur at amino acid 766-775 after the C-helix of the EGFR kinase domain, and a few occur at amino acid 762-764. Mobocertinib is the only EGFR small molecule inhibitor that received FDA single-arm accelerated approval for marketing on September 15, 2021. The ORR for patients with EGFR exon 20 insertion mutations is 28%, and the DOR is 17.5 months. However, on October 2, 2023, Takeda Pharmaceutical's official website announced that because the Phase III randomized controlled trial EXCLAIM-2 of mobocertinib versus platinum-containing chemotherapy did not reach the preset clinical endpoint, it took the initiative to withdraw mobocertinib from the market worldwide. In addition, other marketed EGFR inhibitors are resistant to EGFR exon 20 insertion mutations, have poor efficacy, and an ORR of 0-28%. Amivantamab is an EGFR / c-Met dual antibody that was approved by the FDA on May 21, 2021, with an ORR of 40% and a DOR of 11.1 months. However, 64% of patients experienced infusion-related adverse reactions.

[0010] Therefore, it is of great significance to develop a new generation of EGFR inhibitors that can target both EGFR sensitive mutations and EGFR resistant mutations and are selective for wild-type EGFR. Summary of the invention

[0011] In order to solve the defects of the prior art, the present invention aims to provide an aminoheteroaryl macrocyclic compound and a preparation method and application thereof. The aminoheteroaryl macrocyclic compound has good EGFR inhibitory activity and high selectivity for wild-type EGFR.

[0012] The present invention is achieved through the following technical solutions.

[0013] In the first aspect, the present invention provides an aminoheteroaryl macrocyclic compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof.

[0014]

[0015]

[0016] Wherein, in Formula I,

[0017] The A ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and the M ring through two different atoms, respectively;

[0018] The E ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0019] The M ring is a 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, and the 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl is connected to the A ring and X2 through 2 different atoms;

[0020] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 The heteroalkenylene group is optionally substituted by one or more identical or different R 5 replace;

[0021] X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, S, C(=O) or S(=O)(=W 1 );

[0022] R 1 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′;

[0023] R 2 , R 3 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PRe1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0024] Or two R 2 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl being optionally substituted with one or more R′;

[0025] R 4 for

[0026] R 5 Each is independently a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0027] Or two R 5together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′;

[0028] R 1a , R 2a Each independently does not exist or is each independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 、S(=O)(=W 1 )NR e1 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 OR P(=O)OR e2 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0029] or R 2 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0030] or R 3 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0031] R 3aFor hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0032] or R 2a and R 3aTogether with the attached C atom, it forms a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0033] or R 2 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0034] or R 3 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0035] R' is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR f1 、OC(=O)R f1 、OC(=O)NR f1 R f2 、OS(=O)(=W 1 )R f1 、OS(=O)(=W 1 )NR f1 R f2 , SR f1 、S(=O)(=W 1 )R f1 、S(=O)(=W 1 )NR f1 R f2 NR f1 R f2 NR f1 C(=O)R f2 NR f1 S(=O)(=W 1 )R f2 NR f1 C(=O)OR f2 NR f1 C(=O)NR f2 、C(=O)R f1、C(=O)NR f1 、C(=O)OR f1 、-(O)(OR f1 2. PR f1 R f2 、P(=O)R f1 R f2 、P(=O)2R f1 R f2 、P(=O)OR f2 or oxo (=O);

[0036] R e1 , R e2 , R f1 , R f2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted by one or more R″;

[0037] or R e1 and R e2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0038] or R f1 and R f2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0039] R″ is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 、OC(=O)R g1 、OC(=O)NR g1 R g2 、OS(=O)(=W 1 )R g1 、OS(=O)(=W 1 )NR g1 R g2 , SR g1 、S(=O)(=W 1 )R g1 、S(=O)(=W 1 )NR g1 R g2 NR g1 R g2 NR g1 C(=O)R g2 NR g1 S(=O)(=W 1 )R g2 NR g1 C(=O)OR g2 NR g1 C(=O)NR g2 、C(=O)R g1 、C(=O)NR g1 、C(=O)OR g1 、-(O)(OR g1 2. PR g1 R g2 、P(=O)R g1 R g2 、P(=O)2R g1 R g2 、P(=O)OR g2 or oxo (=O);

[0040] R g1 and R g2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl or 3-12 membered cycloalkyl;

[0041] W 1 None, O or NR g1 ;

[0042] Y is N or C;

[0043] represents a single or double bond;

[0044] R 30 for hydrogen atoms, deuterium atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 3-6 Cycloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more R'; or, two R 30 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0045] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0046] Or, two R 20 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0047] Or, R 20 and R 50 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0048] Or, R 40 and R 60 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0049] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0050] p is independently 1 or 2.

[0051] On the other hand, the present invention also provides an aminoheteroaryl macrocyclic compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof

[0052] Wherein, in Formula I,

[0053] The A ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and the M ring through two different atoms, respectively;

[0054] The E ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0055] The M ring is a 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, and the 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl is connected to the A ring and X2 through 2 different atoms;

[0056] L2 is C 1-6 Alkylene, C2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 The heteroalkenylene group is optionally substituted by one or more identical or different R 5 replace;

[0057] X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, S, C(=O) or S(=O)(=W 1 );

[0058] R 1 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′;

[0059] R 2 , R 3 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0060] Or two R 2 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl being optionally substituted with one or more R′;

[0061] R 4 For R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-12 membered cycloalkyl, wherein R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 )p -C 0-4 Alkyl-4-12 membered cycloalkyl is optionally substituted with one or more R';

[0062] R 5 Each is independently a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)ORe2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0063] Or two R 5 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′;

[0064] R 1a , R 2a Each independently does not exist or each independently is a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 、S(=O)(=W 1 )NR e1 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 OR P(=O)OR e2 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0065] or R 2 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0066] or R 3 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0067] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NRe1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0068] or R 2a and R 3a Together with the attached C atom, it forms a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0069] or R 2 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0070] or R 3 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0071] R' is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR f1 、OC(=O)R f1 、OC(=O)NR f1 R f2 、OS(=O)(=W 1 )R f1 、OS(=O)(=W 1 )NR f1 R f2, SR f1 、S(=O)(=W 1 )R f1 、S(=O)(=W 1 )NR f1 R f2 NR f1 R f2 NR f1 C(=O)R f2 NR f1 S(=O)(=W 1 )R f2 NR f1 C(=O)OR f2 NR f1 C(=O)NR f2 、C(=O)R f1 、C(=O)NR f1 、C(=O)OR f1 、-(O)(OR f1 2. PR f1 R f2 、P(=O)R f1 R f2 、P(=O)2R f1 R f2 、P(=O)OR f2 or oxo (=O);

[0072] R e1 , R e2 , R f1 , R f2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted by one or more R″;

[0073] or R e1 and R e2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0074] or R f1 and R f2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0075] R″ is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 、OC(=O)R g1 、OC(=O)NR g1 R g2 、OS(=O)(=W 1 )R g1 、OS(=O)(=W 1 )NR g1 R g2 , SR g1 、S(=O)(=W 1 )R g1 、S(=O)(=W 1 )NR g1 R g2 NR g1 R g2 NR g1 C(=O)R g2 NR g1 S(=O)(=W 1 )R g2 NR g1 C(=O)OR g2 NR g1 C(=O)NR g2 、C(=O)R g1 、C(=O)NR g1 、C(=O)OR g1 、-(O)(OR g1 2. PR g1 Rg2 、P(=O)R g1 R g2 、P(=O)2R g1 R g2 、P(=O)OR g2 or oxo (=O);

[0076] R g1 and R g2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl or 3-12 membered cycloalkyl;

[0077] W 1 None, O or NR g1 ;

[0078] Y does not exist or is N or C;

[0079] R 20 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more R'; or, two R 20 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0080] R 30 for hydrogen atoms, deuterium atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C3-6 Cycloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more R'; or, two R 30 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0081] Or, R 20 and R 50 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0082] Or, R 40 and R 60 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0083] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0084] p is independently 1 or 2.

[0085] In certain embodiments, in Formula I,

[0086] The A ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and the M ring through two different atoms, respectively;

[0087] The E ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0088] The M ring is a 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, and the 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl is connected to the A ring and X2 through 2 different atoms;

[0089] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 2-6 The heteroalkenylene group is optionally substituted by one or more identical or different R 5 replace;

[0090] X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, S, C(=O) or S(=O)(=W 1 );

[0091] R 1 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′;

[0092] R 2 , R 3 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0093] Or two R 2 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl being optionally substituted with one or more R′;

[0094] R 4 for

[0095] R 5 Each is independently a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0096] Or two R 5 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′;

[0097] R 1a , R 2a Each independently does not exist or each independently is a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 、S(=O)(=W 1 )NR e1 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 OR P(=O)OR e2 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0098] or R 2 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0099] or R 3 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0100] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2, SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′;

[0101] or R 2a and R 3a Together with the attached C atom, it forms a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0102] or R 2 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0103] or R 3 and R 3aTogether with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0104] R' is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR f1 、OC(=O)R f1 、OC(=O)NR f1 R f2 、OS(=O)(=W 1 )R f1 、OS(=O)(=W 1 )NR f1 R f2 , SR f1 、S(=O)(=W 1 )R f1 、S(=O)(=W 1 )NR f1 R f2 NR f1 R f2 NR f1 C(=O)R f2 NR f1 S(=O)(=W 1 )R f2 NR f1 C(=O)OR f2 NR f1 C(=O)NR f2 、C(=O)R f1 、C(=O)NR f1 、C(=O)OR f1 、-(O)(OR f1 2. PR f1 R f2 、P(=O)R f1 R f2 、P(=O)2R f1 R f2 、P(=O)OR f2 or oxo (=O);

[0105] R e1 , R e2 , R f1 , R f2are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl are optionally substituted by one or more R″;

[0106] or R e1 and R e2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0107] or R f1 and R f2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0108] R″ is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 、OC(=O)R g1 、OC(=O)NR g1 R g2 、OS(=O)(=W 1 )R g1 、OS(=O)(=W 1 )NR g1 R g2, SR g1 、S(=O)(=W 1 )R g1 、S(=O)(=W 1 )NR g1 R g2 NR g1 R g2 NR g1 C(=O)R g2 NR g1 S(=O)(=W 1 )R g2 NR g1 C(=O)OR g2 NR g1 C(=O)NR g2 、C(=O)R g1 、C(=O)NR g1 、C(=O)OR g1 、-(O)(OR g1 2. PR g1 R g2 、P(=O)R g1 R g2 、P(=O)2R g1 R g2 、P(=O)OR g2 or oxo (=O);

[0109] R g1 and R g2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl or 3-12 membered cycloalkyl;

[0110] W 1 None, O or NR g1 ;

[0111] Y is N or C; provided that, when Y is C, the M ring is pyridine, pyrimidine, pyridone, pyridazine, oxazole, thiazole, imidazole, pyrrole, triazole or pyridine N-oxide;

[0112] R 30 for hydrogen atoms, deuterium atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0113] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0114] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0115] p is independently 1 or 2.

[0116] In certain embodiments, the compound of formula I is further represented by formula II:

[0117]

[0118] Among them, A, M, X1, X2, L2, R 1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , Y, m, n, t, p are defined as above;

[0119] --- means no or single key;

[0120] U 1 Not present or N or CH;

[0121] U 2 Not present or N or CH;

[0122] U 3 N, C, NR 100 , O, S or C(=O);

[0123] U 4 and U 5 are each independently N or C, and U 4 and U 5 Not all are N;

[0124] U 6 N or CH;

[0125] U 7 C, N, NR 200 ,O,S,C(=O),C(=O)O,C(=O)NR 300 , OC(=O) or NR 300 C(=O);

[0126] R 100 , R 200 or R 300 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group;

[0127] When U 1 When it does not exist, U 2 and U 7 Connected by single or double bonds; when U 2 When it does not exist, U 1 and U 3 connected by single or double bonds;

[0128] When U 1 and U 2 When N or CH, U 1 , U 2 , U 3 , U 4 , U 5 and U 7 At most three of them are N at the same time;

[0129] When Y is C, the M ring is pyridine, pyrimidine, pyridone, pyridazine, oxazole, thiazole, imidazole, pyrroletriazole or pyridine N-oxide.

[0130] In certain embodiments, the compound of formula I is further represented by formula III:

[0131]

[0132] Among them, A, M, X1, X2, L2, R 1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , Y, m, n, t, p are defined as above;

[0133] U 1 , U 2 or U 6 are each independently N or CH.

[0134] In certain embodiments, the compound of formula I is further represented by formula IV:

[0135]

[0136] Among them, X1, X2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,m,p are defined as above;

[0137] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6The heteroalkenylene group is optionally substituted with 2 or more identical or different R 5 replace;

[0138] At least two independent R 5 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′;

[0139] U 1 , U 2 or U 6 are each independently N or CH;

[0140] U 8 N, CR 1 , O, S or C(=O);

[0141] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0142] U 11 N, CR 1 , O, S or C(=O);

[0143] R 3a ' is a hydrogen atom, a deuterium atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, OR e1 , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0144] R 3b ' is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0145] R 5 , R′, R e1 The definition of is as described above.

[0146] In certain embodiments, the compound of formula I is further represented by formula V:

[0147]

[0148] Among them, X1, X2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,m,p are defined as above;

[0149] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 The heteroalkenylene group is optionally substituted with one or more identical or different R 5 replace;

[0150] U 1 , U 2 or U 6 are each independently N or CH;

[0151] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0152] U 10CR 1 ′;

[0153] U 11 N, CR 1 , O, S or C(=O);

[0154] R 1 ' is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′;

[0155] R 3a ' is a hydrogen atom, a deuterium atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, OR e1 , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0156] R 3b ' is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0157] R 5 , R′, R e1 The definition of is as described above.

[0158] In certain embodiments, in Formula I,

[0159] The E ring is a 9-10 membered heteroaryl group, and the 9-10 membered heteroaryl group is connected to NH and X1 through two different atoms respectively;

[0160] Preferably, the E ring is

[0161] More preferably, the E ring is selected from

[0162] Most preferably, the E ring is selected from

[0163] Among them, --- or -- means no or single bond; U 1 , U 2 , U 3 , U 4 , U 5 , U 6 or U 7 The definition of is as described above.

[0164] In certain embodiments, Ring A is a 5-6 membered heteroaryl;

[0165] Preferably, Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole;

[0166] More preferably, the A ring is selected from the following groups:

[0167] * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop.

[0168] In certain embodiments, the M ring is a 5-6 membered heteroaryl or benzene;

[0169] Preferably, the M ring is pyridine, pyrimidine, pyridazine, imidazole, pyrazole, thiazole, oxazole, triazole, benzene or pyridine N-oxide;

[0170] More preferably, the M ring is selected from the following groups:

[0171]

[0172] * e Indicates the site of connection with the A ring, * f Indicates the site of connection with X2.

[0173] In certain embodiments, L2 is C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, the C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 The heteroalkylene group is optionally substituted with one or more identical or different R 5 replace;

[0174] Preferably, L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, wherein the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0175] In certain embodiments, X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0176] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl is optionally substituted with one or more R';

[0177] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted by one or more R′;

[0178] or R 2a and R 3a Together with the attached C atom, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocyclic group is optionally substituted by one or more R'

[0179] Preferably, X1 is absent or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0180] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0181] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0182] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0183] or R 2a and R 3a Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, which is optionally substituted by one or more R'.

[0184] In certain embodiments, R 1 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl or oxo, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl are optionally substituted by one or more R';

[0185] Preferably, R 1each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group or an oxo group;

[0186] More preferably, R 1 Each is independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0187] In certain embodiments, R 2 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl and 3-12 membered heterocyclyl-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0188] Preferably, R 2Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, and the methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group is optionally substituted by one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups.

[0189] In certain embodiments, R 3 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 Alkyl, Oxo(=O), C(=O)R e1 、C(=O)NR e1 or S(=O)2R e1 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0190] Preferably, R 3are each independently a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group, an oxo group, a C(═O)R e1 、C(=O)NR e1 or S(=O)2R e1 ;

[0191] or R 3 and R 1a Together with the atoms to which it is attached, it forms a pyrrole, imidazole, thiazole, oxazole, isothiazole, isoxazole or pyrazole;

[0192] R e1 is a hydrogen atom, a methyl group, an ethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;

[0193] More preferably, R 3 It is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, C(═O)CH 3 , C(═O)-cyclopropyl group, C(═O)N(CH 3 ) 2 or S(═O) 2-cyclopropyl group.

[0194] In certain embodiments, R 4 for

[0195] In certain embodiments, R 4 For R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered cycloalkyl, wherein R 30 -S(=O)(W 1 )-Y(R20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered cycloalkyl is optionally substituted with one or more R';

[0196] Preferably, R 4 Selected from

[0197] Wherein, Y does not exist or is N or C;

[0198] Y 1 Not present or N or C;

[0199] Y 2 , Y 3 Each independently is NR 70 , N, CR 70 , O or S;

[0200] W 1 None, O or NR g1 ;

[0201] R 20 , R 30 , R 40 , R 50 , R 60 is defined as above;

[0202] R 70 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0203] q1 or q2 are each independently 1, 2 or 3;

[0204] Or, two R 20 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0205] Or, two R 30 Together with the atoms to which it is attached, it forms azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl are optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or halogen;

[0206] Or, R 20 and R 50 Together with the atoms to which they are attached they form azetidinyl, azetidinyl, azetidinyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the azetidinyl, azetidinyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano;

[0207] Or, R 40 and R 60 Together with the atoms to which they are attached, they form azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, which are optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano;

[0208] More preferably, R 4 Selected from

[0209] In certain embodiments, R 5 For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R′;

[0210] Alternatively, a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, 3-6 membered cycloalkyl or oxo substituted;

[0211] Or two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0212] Preferably, R 5 is a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0213] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine is optionally substituted with one or more R′.

[0214] In certain embodiments, R′ is a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group, or an oxo group.

[0215] In certain embodiments, R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 The alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substitution;

[0216] Preferably, R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, methoxy, ethylamino, diethylamino, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms.

[0217] In certain embodiments, R 30 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the amino group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0218] Preferably, R 30 Each is independently a hydrogen atom, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl is optionally substituted by one or more halogen or deuterium atoms.

[0219] In certain embodiments, W 1 None, O or NR g1 ; R g1 is a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group;

[0220] Preferably, W 1 is O.

[0221] In certain embodiments, Y is N or C; provided that, when Y is C, the M ring is pyridine, pyrimidine, pyridone, pyridazine, oxazole, thiazole, imidazole, pyrrole, triazole or pyridine N-oxide;

[0222] Preferably, Y is N.

[0223] In certain embodiments,

[0224] R 3a ' is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group;

[0225] R 3b' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl, an ethyl, a propyl, a trideuterium methyl, a difluoromethyl, a trifluoromethyl, a difluoroethyl, a trifluoroethyl, a vinyl, an ethynyl, a cyclopropyl, a cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl are optionally substituted with one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, an oxo;

[0226] R 1 ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuteriomethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy or oxo.

[0227] In certain embodiments, the compound further has the structure shown in Formula VI:

[0228]

[0229] in,

[0230] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 The heteroalkenylene group is optionally substituted with one or more identical or different R 5 replace;

[0231] R 5 Each is independently a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0232] Or, two R 5 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′;

[0233] q is 1, 2, or 3;

[0234] Y, X1, X2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , U 1 , U 2 , U 6 , U 9 , U 10 , U 11 , R 3a ′、R 3b ′, m, and p are defined as above;

[0235] Preferably, L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, wherein the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0236] R 5 For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6Alkoxy is optionally substituted with one or more R′;

[0237] Or two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0238] More preferably, L2 is Among them, R 5a , R 5b , R 5c , R 5a′ , R 5b′ , R 5c′ Each independently is R 5 ; R 5 The definition is as described above; preferably, R 5a , R 5b , R 5c , R 5a′ , R 5b′ , R 5c′ are independently a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, 3-6 membered cycloalkyl or oxo substituted;

[0239] Or, R 5a and R 5a′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0240] Or, R 5b and R 5b′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0241] Or, R 5c and R 5c′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0242] Or, R 5a and R 5b Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0243] Or, R 5a and R 5c Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0244] Or, R 5b and R 5c Together with the attached atoms, they form a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R'.

[0245] In certain embodiments, the compound further has the structure shown in Formula VII:

[0246]

[0247] Among them, U 12 -N(R 3a ′)-、-C(R 3a ′)=C(R 3a ′)-;

[0248] Y, X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1, p, q, U 1 , U 2 , U 6 , U 9 , U 10 , U 11 , R 3a ′、R 3b ' is defined as above;

[0249] In certain embodiments, in Formula I:

[0250] Ring A is a 5-6 membered heteroaryl group;

[0251] The M ring is a 5-6 membered heteroaryl or benzene;

[0252] The E ring is

[0253] L2 is C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, the C 1-6 Alkylene C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 The heteroalkylene group is optionally substituted with one or more identical or different R 5 replace;

[0254] X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0255] R 1 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group or an oxo group;

[0256] R 2 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl and 3-12 membered heterocyclyl-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0257] R 3 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 Alkyl, Oxo(=O), C(=O)R e1 、C(=O)NR e1 or S(=O)2R e1 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0258] R 4 for

[0259] R 5 For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R′;

[0260] Or two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0261] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl is optionally substituted with one or more R';

[0262] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, the C 1-6 Alkyl, hydroxyl C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted by one or more R′;

[0263] or R 3 and R 1a Together with the atoms to which it is attached, it forms a pyrrole, imidazole, thiazole, oxazole, isothiazole, isoxazole or pyrazole;

[0264] or R 2a and R 3a Together with the attached C atom, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by one or more R′;

[0265] R e1 is a hydrogen atom, a methyl group, an ethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;

[0266] W 1 is none, O or NH;

[0267] Y is N or C; provided that, when Y is C, the M ring is pyridine, pyrimidine, pyridone, pyridazine, oxazole, thiazole, imidazole, pyrrole, triazole or pyridine N-oxide;

[0268] --- means no or single key;

[0269] U 1 Not present or N or C;

[0270] U 2 Not present or N or C;

[0271] U 3 is C or C(=O);

[0272] U 4 and U 5 Each independently is C;

[0273] U 6 N or CH;

[0274] U 7 is C, N, N-methyl, N-ethyl or N-cyclopropyl;

[0275] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 The alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substitution;

[0276] R 30 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the amino group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0277] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0278] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0279] p is independently 1 or 2.

[0280] In certain embodiments, in Formula I:

[0281] Ring A is a 5-6 membered heteroaryl group;

[0282] The M ring is a 5-6 membered heteroaryl or benzene;

[0283] The E ring is

[0284] L2 is C1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, the C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 The heteroalkylene group is optionally substituted with one or more identical or different R 5 replace;

[0285] X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0286] R 1 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group or an oxo group;

[0287] R 2 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl and 3-12 membered heterocyclyl-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0288] R 3 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 Alkyl, Oxo(=O), C(=O)R e1 、C(=O)NR e1 or S(=O)2R e1 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0289] R 4 for

[0290] R 5 For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, C0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R′;

[0291] Or two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0292] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl is optionally substituted with one or more R';

[0293] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted by one or more R′;

[0294] or R 3 and R 1a Together with the atoms to which it is attached, it forms a pyrrole, imidazole, thiazole, oxazole, isothiazole, isoxazole or pyrazole;

[0295] or R 2a and R 3a Together with the attached C atom, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by one or more R′;

[0296] Re1 is a hydrogen atom, a methyl group, an ethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;

[0297] W 1 is none, O or NH;

[0298] Y is N or C;

[0299] --- means no or single key;

[0300] U 1 Not present or N or C;

[0301] U 2 Not present or N or C;

[0302] U 3 is C or C(=O);

[0303] U 4 and U 5 Each independently is C;

[0304] U 6 N or CH;

[0305] U 7 is C, N, N-methyl, N-ethyl or N-cyclopropyl;

[0306] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 The alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substitution;

[0307] R 30Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the amino group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0308] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0309] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0310] p is independently 1 or 2.

[0311] In certain embodiments, in Formula VI or Formula VII,

[0312] L2 is C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene, the C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 The heteroalkylene group is optionally substituted with one or more identical or different R 5 replace;

[0313] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0314] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0315] R 2 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl and 3-12 membered heterocyclyl-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0316] R 5 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R′;

[0317] Or, two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′;

[0318] R 1a , R 2a are independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl is optionally substituted with one or more R';

[0319] R 3a For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted by one or more R′;

[0320] or R 2 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0321] or R 3 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0322] or R 2 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0323] or R 3 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′;

[0324] or R 2a and R 3a Together with the attached C atom, it forms a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0325] Y is N or C;

[0326] W 1 is none, O or NH;

[0327] U 1 N or C;

[0328] U 2 N or C;

[0329] U 6 N or CH;

[0330] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0331] U 10 CR 1 ′;

[0332] U 11 N, CR 1 , O, S or C(=O);

[0333] U 12 -N(R 3a ′)-、-C(R 3a ′)=C(R 3a ′)-;

[0334] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2Alkyl-3-12 membered cycloalkyl or C 0-2 The alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substitution;

[0335] Or, two R 20 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0336] R 30 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0337] Or, two R 30 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′;

[0338] R 3a ' is a hydrogen atom, a deuterium atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, OR e1 , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0339] R 3b ' is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′;

[0340] R 1 ' is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′;

[0341] m is 0, 1, 2, 3, or 4;

[0342] p is each independently 1 or 2;

[0343] q is 1, 2 or 3.

[0344] In other specific embodiments,

[0345] Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole;

[0346] Ring M is pyridine, pyrimidine, pyridazine, imidazole, pyrazole, thiazole, oxazole, triazole, benzene or pyridine N-oxide;

[0347] The E ring is

[0348] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0349] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0350] X2 is -C(R2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0351] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group;

[0352] R 2 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups;

[0353] R 3 is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, a C(═O)CH 3 , a C(═O)-cyclopropyl group, a C(═O)N(CH 3 ) 2 group or a S(═O) 2-cyclopropyl group;

[0354] R 4 for

[0355] R 5 is a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0356] Or two R 5 together with the atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine being optionally substituted with one or more R′;

[0357] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0358] R 3ais a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0359] or R 2a and R 3a Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, wherein the cyclopropyl, cyclobutyl, cyclopentylcyclohexyl, oxirane or oxetanyl is optionally substituted with one or more R′;

[0360] W 1 is none, O or NH;

[0361] Y is N or C; provided that when Y is C, the M ring is pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole or pyridine N-oxide;

[0362] --- means no or single key;

[0363] U 1 N or C;

[0364] U 2 N or C;

[0365] U 3 , U 4 and U 5 Each independently is C;

[0366] U 6 N or CH;

[0367] U 7 is C;

[0368] R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms;

[0369] R 30each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms;

[0370] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0371] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0372] p is independently 1 or 2.

[0373] In other specific embodiments, in Formula IV,

[0374] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0375] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0376] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0377] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group or a cyclopropyl group;

[0378] R 2each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups;

[0379] R 5 is a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0380] At least two R 5 together with the atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine being optionally substituted with one or more R′;

[0381] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0382] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0383] or R 2a and R 3a together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl being optionally substituted with one or more R′;

[0384] W 1 is none, O or NH;

[0385] U 1 N or C;

[0386] U 2 N or C;

[0387] U 6 N or CH;

[0388] U 8 N, CR 1 , O, S or C(=O);

[0389] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0390] U 11 N, CR 1 , O, S or C(=O);

[0391] R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms;

[0392] R 30 each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms;

[0393] R 3a ' is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group;

[0394] R 3b ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl, an ethyl, a propyl, a trideuterium methyl, a difluoromethyl, a trifluoromethyl, a difluoroethyl, a trifluoroethyl, a vinyl, an ethynyl, a cyclopropyl, a cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl are optionally substituted with one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, an oxo;

[0395] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0396] m is 0, 1, 2, 3, or 4;

[0397] p is independently 1 or 2.

[0398] In other specific embodiments, in Formula V,

[0399] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0400] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0401] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0402] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group, an ethylene group, an acetylene group or a cyclopropyl group;

[0403] R 2each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups;

[0404] R 5 is a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0405] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0406] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0407] or R 2a and R 3a together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl being optionally substituted with one or more R′;

[0408] W 1 is none, O or NH;

[0409] U 1 N or C;

[0410] U 2 N or C;

[0411] U 6 N or CH;

[0412] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0413] U 10 CR 1 ′;

[0414] U 11 N, CR 1 , O, S or C(=O);

[0415] R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms;

[0416] R 30 each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms;

[0417] R 3a ' is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group;

[0418] R 3b' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl, an ethyl, a propyl, a trideuterium methyl, a difluoromethyl, a trifluoromethyl, a difluoroethyl, a trifluoroethyl, a vinyl, an ethynyl, a cyclopropyl, a cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl are optionally substituted with one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, an oxo;

[0419] R 1 ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuterium, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy or oxo;

[0420] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0421] m is 0, 1, 2, 3, or 4;

[0422] p is independently 1 or 2.

[0423] In other specific embodiments, in Formula VI or Formula VII,

[0424] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0425] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0426] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0427] R 2each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups;

[0428] R 5 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0429] Or, two R 5 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine is optionally substituted with one or more R′;

[0430] R 1a , R 2a are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0431] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0432] or R 2a and R 3a together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl being optionally substituted with one or more R′;

[0433] Y is N or C;

[0434] W 1 is none, O or NH;

[0435] U 1 N or C;

[0436] U 2 N or C;

[0437] U 6 N or CH;

[0438] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0439] U 10 CR 1 ′;

[0440] U 11 N, CR 1 , O, S or C(=O);

[0441] U 12 -N(R 3a ′)-、-C(R 3a ′)=C(R 3a ′)-;

[0442] R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms;

[0443] R 30 each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms;

[0444] Or, two R 20Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0445] R 3a ' is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group;

[0446] R 3b ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl, an ethyl, a propyl, a trideuterium methyl, a difluoromethyl, a trifluoromethyl, a difluoroethyl, a trifluoroethyl, a vinyl, an ethynyl, a cyclopropyl, a cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl are optionally substituted with one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, an oxo;

[0447] R 1 ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuterium, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy or oxo;

[0448] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0449] m is 0, 1, 2, 3, or 4;

[0450] p is each independently 1 or 2;

[0451] q is 1, 2 or 3.

[0452] In some further specific embodiments,

[0453] Ring A is selected from the following groups:

[0454] * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop;

[0455] The M ring is selected from the following groups:

[0456]

[0457] * e Indicates the site of connection with the A ring, * f represents the site of connection with X2;

[0458] The E ring is

[0459] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0460] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0461] X2 is -C(R 2a )(R 3a )-, O, C(=O) or S(=O)2;

[0462] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0463] R 2 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group or a methoxy group, wherein the methyl group, the ethyl group or the methoxy group is optionally substituted by one or more halogen groups;

[0464] R 3 is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, a C(═O)N(CH 3 ) 2 group or a S(═O) 2 -cyclopropyl group;

[0465] R 4 for

[0466] R5 is a deuterium atom, a halogen, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group or an oxo group;

[0467] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl, cyclopropyl;

[0468] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0469] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0470] or R 2a and R 3a Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, oxirane or oxetanyl group, wherein the cyclopropyl, cyclobutyl, oxirane or oxetanyl group is optionally substituted with one or more halogen, methyl or hydroxyl groups;

[0471] U 1 N or C;

[0472] U 2 N or C;

[0473] U 3 , U 4 and U 5 Each independently is C;

[0474] U 6 N or CH;

[0475] U 7 is C;

[0476] R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, deuterated methyl or oxo;

[0477] R 30Each is independently a hydrogen atom, amino, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl;

[0478] W 1 is O;

[0479] Y is N or C;

[0480] --- or -- means no or single key;

[0481] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0482] p is independently 1 or 2.

[0483] In some further specific embodiments,

[0484] Ring A is selected from the following groups:

[0485] * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop;

[0486] The M ring is selected from the following groups:

[0487] * e Indicates the site of connection with the A ring, * f represents the site of connection with X2;

[0488] The E ring is selected from

[0489] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0490] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0491] X2 is -C(R 2a )(R 3a )-, O, C(=O) or S(=O)2;

[0492] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0493] R 2 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group or a methoxy group, wherein the methyl group, the ethyl group or the methoxy group is optionally substituted by one or more halogen groups;

[0494] R 3 is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, a C(═O)N(CH 3 ) 2 group or a S(═O) 2 -cyclopropyl group;

[0495] R 4 Selected from

[0496] R 5 is a deuterium atom, a halogen, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group or an oxo group;

[0497] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl, cyclopropyl;

[0498] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0499] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0500] or R 2a and R 3a Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, oxirane or oxetanyl group, wherein the cyclopropyl, cyclobutyl, oxirane or oxetanyl group is optionally substituted with one or more halogen, methyl or hydroxyl groups;

[0501] m, n, and t are each independently 0, 1, 2, 3, or 4.

[0502] In some other specific embodiments, in Formula VI or Formula VII,

[0503] L2 is Among them, R 5a , R 5b , R 5c , R5a′ , R 5b′ , R 5c′ Each independently is R 5 ; R 5 is a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0504] Or, R 5a and R 5a′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0505] Or, R 5b and R 5b′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0506] Or, R 5c and R 5c′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0507] Or, R 5a and R 5b together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0508] Or, R 5a and R 5ctogether with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0509] Or, R 5b and R 5c together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′;

[0510] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0511] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0512] R 2 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups;

[0513] R 5 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group;

[0514] Or, two R 5Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine is optionally substituted with one or more R′;

[0515] R 1a , R 2a are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0516] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0517] or R 2a and R 3a together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl being optionally substituted with one or more R′;

[0518] Y is N or C;

[0519] W 1 is none, O or NH;

[0520] U 1 N or C;

[0521] U 2 N or C;

[0522] U 6 N or CH;

[0523] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0524] U 10 CR 1 ′;

[0525] U 11 N, CR 1 , O, S or C(=O);

[0526] U 12 -N(R 3a ′)-、-C(R3a ′)=C(R 3a ′)-;

[0527] R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms;

[0528] R 30 each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms;

[0529] Or, two R 20 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0530] R 3a ' is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group;

[0531] R 3b' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl, an ethyl, a propyl, a trideuterium methyl, a difluoromethyl, a trifluoromethyl, a difluoroethyl, a trifluoroethyl, a vinyl, an ethynyl, a cyclopropyl, a cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, an oxirane, an oxetane, an aziridine, an azetidinyl are optionally substituted with one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, an oxo;

[0532] R 1 ' is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuterium, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy or oxo;

[0533] R′ is a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0534] m is 0, 1, 2, 3, or 4;

[0535] p is each independently 1 or 2;

[0536] q is 1, 2 or 3.

[0537] In some further specific embodiments,

[0538] Ring A is selected from the following groups:

[0539] * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop;

[0540] The M ring is selected from the following groups:

[0541] * e Indicates the site of connection with the A ring, * f represents the site of connection with X2;

[0542] The E ring is selected from

[0543] L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace;

[0544] X1 does not exist or is NR 1a ,-C(R 2a )(R 3a )-or O;

[0545] X2 is -C(R 2a )(R 3a )-, O, C(=O) or S(=O)2;

[0546] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0547] R 2 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group or a methoxy group, wherein the methyl group, the ethyl group or the methoxy group is optionally substituted by one or more halogen groups;

[0548] R 3 is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, a C(═O)N(CH 3 ) 2 group or a S(═O) 2 -cyclopropyl group;

[0549] R 4 Selected from

[0550] R 5 is a deuterium atom, a halogen, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group or an oxo group;

[0551] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl, cyclopropyl;

[0552] R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group;

[0553] R 3ais a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0554] or R 2a and R 3a Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, oxirane or oxetanyl group, wherein the cyclopropyl, cyclobutyl, oxirane or oxetanyl group is optionally substituted with one or more halogen, methyl or hydroxyl groups;

[0555] m, n, and t are each independently 0, 1, 2, 3, or 4.

[0556] In some more specific embodiments, the compounds represented by Formulas I to V are selected from the following compounds:

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565] In a second aspect, in certain embodiments, the present invention provides a method for preparing a compound of formula II, the method comprising the following reaction steps:

[0566] (1) Compound II-1 undergoes a coupling reaction with compound II-2 to form compound II-3;

[0567] (2) Compound II-3 and compound II-4 undergo coupling reaction to form compound II-5;

[0568] (3) deprotecting compound II-5 to form compound II-6;

[0569] (4) Compound II-6 undergoes Mitsunobu reaction to form a compound represented by Formula II;

[0570]

[0571] Among them, A, M, X1, X2, L2, R1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 The definitions of , Y, m, n, t, and p are as described above.

[0572] In certain embodiments, the present invention provides a method for preparing a compound of formula III, comprising the following reaction steps:

[0573] (1) Compound III-1 undergoes a coupling reaction with compound III-2 to form compound III-3;

[0574] (2) Compound III-3 undergoes a coupling reaction with compound II-4 to form compound III-5;

[0575] (3) deprotecting compound III-5 to form compound III-6;

[0576] (4) Compound III-6 undergoes Mitsunobu reaction to form a compound represented by formula III;

[0577]

[0578] Among them, A, M, X1, X2, L2, R 1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , Y, U 1 , U 2 , U 6 , m, n, t, p are defined as above;

[0579] G is a protecting group, and the protecting group is PMB, SEM, methyl, Boc, Cbz and the like.

[0580] In certain embodiments, the present invention provides a method for preparing a compound of formula IV, comprising the following reaction steps:

[0581] (1) Compound IV-1 undergoes a coupling reaction with compound IV-2 to form compound IV-3;

[0582] (2) Compound IV-3 and compound IV-4 undergo coupling reaction to form compound IV-5;

[0583] (3) deprotection of compound IV-5 to form compound IV-6;

[0584] (4) Compound IV-6 undergoes Mitsunobu reaction to form a compound represented by Formula IV;

[0585]

[0586] Among them, X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , U 1 , U 2 , U 6 , U 8 , U 9 , U 11 , R 3a ′、R 3b The definitions of ′, m, and p are as described above.

[0587] In certain embodiments, the present invention provides a method for preparing a compound of formula V, comprising the following reaction steps:

[0588] (1) Compound V-1 and Compound V-2 undergo a coupling reaction to form Compound V-3;

[0589] (2) Compound V-3 and Compound V-4 undergo a coupling reaction to form Compound V-5;

[0590] (3) deprotecting compound V-5 to form compound V-6;

[0591] (4) Compound V-6 undergoes Mitsunobu reaction to form a compound represented by Formula V;

[0592]

[0593] Among them, X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W1 , U 1 , U 2 , U 6 , U 9 , U 10 , U 11 , R 3a ′、R 3b The definitions of ′, m, and p are as described above.

[0594] In certain embodiments, the present invention provides a method for preparing a compound of formula VII, comprising the following reaction steps:

[0595] (1) Compound VII-1 undergoes a coupling reaction with compound VII-2 to form compound VII-3;

[0596] (2) Compound VII-3 and compound VII-4 undergo a coupling reaction to form compound VII-5;

[0597] (3) deprotecting compound VII-5 to form compound VII-6;

[0598] (4) Compound VII-6 undergoes Mitsunobu reaction to form a compound represented by Formula VII;

[0599]

[0600] Among them, X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , U 1 , U 2 , U 6 , U 9 , U 10 , U 11 , U 12 , R 3a ′、R 3b The definitions of ′, m, and p are as described above.

[0601] In certain embodiments, the present invention provides another method for preparing the intermediate VII-3 compound, which comprises the following reaction steps:

[0602] (1) Compound VII-7 undergoes a coupling reaction with compound VII-2 to form compound VII-8;

[0603] (2) Compound VII-8 is iodinated to form compound VII-9;

[0604] (3) Compound VII-9 undergoes Suzuki coupling reaction with compound VII-10 or VII-11 to form compound VII-12;

[0605] (4) Compound VII-12 is reduced to form compound VII-13;

[0606] (5) protecting group on compound VII-13 to form compound of formula VII-3;

[0607]

[0608] Among them, X m is X1, or X1 containing a double bond;

[0609] X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 , U 1 , U 2 , U 6 , U 9 , U 10 , U 11 , U 12 , R 3a ′、R 3b The definitions of ′, m, and p are as described above.

[0610] In a third aspect, the present invention provides a pharmaceutical composition comprising the above compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient;

[0611] Preferably, the pharmaceutical composition is in the form of tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, or sprays.

[0612] In a fourth aspect, the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient in treating diseases mediated by abnormal EGFR;

[0613] Preferably, the disease is a tumor disease;

[0614] More preferably, the tumor diseases include: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

[0615] In a fifth aspect, the present invention provides a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

[0616] The patient is preferably a mammal, and the mammal is preferably a human.

[0617] In certain embodiments, the administration route includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.

[0618] In some embodiments, the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma.

[0619] The compounds or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions of the present invention can enter the body through any suitable route, such as oral, intravenous, intranasal, external, intramuscular, intradermal, transdermal or subcutaneous routes.

[0620] In certain embodiments, the compounds provided herein or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope labels, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions can be prepared into dosage forms suitable for drug release, and can be administered by injection (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intraframe, intracardiac, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes (e.g., oral, enteral, oral, nasal, intranasal, mucosal, epidermal, plaster, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).

[0621] Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, medical patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and the preparation methods and processes are well known, such as provided by Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0622] In certain embodiments, EGFR abnormality refers to EGFR mutation, EGFR amplification, or EGFR overexpression.

[0623] Preferably, EGFR mutation refers to amino acid deletion, change and / or insertion of other amino acids at any position of the EGFR sequence, generally occurring in intracellular exons 18-21 or extracellular exons 2-16.

[0624] More preferably, the EGFR mutation occurs in the kinase region of exons 18-21, including but not limited to: point mutations in exon 18 such as E709K / Q / A / G / V, G719C / S / A / R, G724S, etc., deletions, point mutations and / or insertion mutations in exon 19 such as delE746_A750, delE746_E749, A750P, delE746_A750insQP, delE746_A750insRP, etc., exon 20 Point mutations, insertion mutations such as S768I, V769_D770insASV, D770_N771insSVD, D770_N771insG, A763_Y764insFQEA, etc., exon 21 point mutations such as L858R, L861Q / R, etc., and secondary drug-resistant mutations such as T790M, L792H, G796R / S / D, C797S / G / N, L718P / Q / V, etc. In addition, EGFR mutations also include these mutation combinations.

[0625] In certain embodiments, the compound or pharmaceutical composition of the present invention can be administered simultaneously with one or more other pharmacologically active substances, so that an additive or even synergistic effect can be achieved in vivo. For example, the compound of the present invention can be combined with other pharmacologically active substances into a pharmaceutical composition, or administered simultaneously as a separate composition, or administered sequentially as a separate composition. Other pharmacologically active substances that can be used simultaneously with the compounds of the present invention for the treatment of cancer include but are not limited to: 1) EGFR family inhibitors, single / double antibodies or ADCs, such as osimertinib, ametinib, vometinib, befortinib, rizitinib, ruetinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emmetuzumab, detrastuzumab, etc.; 2) downstream pathway or other pathway target inhibitor single / double antibodies or ADCs, etc., the targets include but are not limited to MEK, RET, PI3K, mTOR, c-Met, PARP or mitotic kinase inhibitors (such as CDK4 / 6), etc.Such as: Trametinib, Bimetinib, Selumetinib, Palacitinib, Idranib, Copanlisib, Duvelisib, Alpelisib, Umbralisib, Parsaclisib, Rapamycin, Temsirolimus, Everolimus, Capmatinib, Tepotinib, Saivotinib, Gumetinib, Berretinib, Cabozantinib, Emibetuzumab, Telisotuzumab, Niraparib, Palbociclib, Ribociclib, Abemaciclib, etc. ; 3) anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) apoptosis inducers (such as Bcl-2), such as obatoclax, venetoclax, etc.; 5) chemotherapeutic drugs, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carboplatin, amustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, daunomycin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole Azoles, leucovorin, pentostatin, mithramycin, procarbazine, raltitrexed, porfibril sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, cyclohexyl lomustine, nitrogen mustard, medroxyprogesterone, megestrol acetate, melphalan, mercaptopurine, sodium thioethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triamine thionyl, methyl chloride, topotecan titanocene, retinoic acid, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0626] In certain embodiments, the compounds provided by the present invention can be used simultaneously with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents for reversing multidrug resistance of tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

[0627] In certain embodiments, the compounds provided by the invention can be used simultaneously with non-chemical methods to treat cancer. In certain embodiments, the compounds provided by the invention can be used simultaneously with radiotherapy. In certain embodiments, the compounds provided by the invention can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy or several of the above therapies.

[0628] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0629] It is particularly important to point out that similar substitutions and modifications made to the present invention are obvious to those skilled in the art, and they are all considered to be included in the present invention. Relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments.

[0630] If no specific conditions are specified in the present invention, the process is carried out under conventional conditions or conditions recommended by the manufacturer. The raw materials or excipients used, as well as the reagents or instruments used, whose manufacturers are not specified, are all conventional products that can be obtained commercially.

[0631] Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention.

[0632] --- means no or single key.

[0633] Indicates the connection site.

[0634] The minimum and maximum carbon content of a hydrocarbon group is indicated by a prefix, for example, the prefix (C a-b )alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C 1-6 ) Alkyl refers to an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or linear.

[0635] The atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.

[0636] "Bridged ring" refers to a polycyclic group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and the ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or SO2. Preferably, there are 7-10 rings.

[0637] "Spirocyclic ring" refers to a polycyclic group in which any two rings share a carbon atom, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and the ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or SO2. Preferably, it has 5-10 rings.

[0638] Fused ring: refers to a polycyclic group in which each ring shares two adjacent atoms with other rings in the system.

[0639] According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0640] A cyclic group can be bonded to another group in a variety of ways. If the bonding mode is not specified, it is meant to include all possible modes. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

[0641] "Alkyl" refers to a linear or branched, monovalent saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and other similar groups. 1-8 Alkyl. More preferably C 1-6 Alkyl. More preferably C 1-4 Alkyl. The alkyl group may be substituted with one or more substituents or may be unsubstituted. When substituted, the substituents may be substituted at any point of attachment. The substituents are preferably the following groups:

[0642] Deuterium atoms, halogens, cyano, nitro, azido, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0643] "Heteroalkyl" refers to a linear or branched, monovalent saturated hydrocarbon group in which carbon atoms are substituted by one or more heteroatoms selected from O, N, S, S(=O), S(=O)2 or Si, including but not limited to -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -O-CH2-CH3.

[0644] "Heteroalkylene" refers to a divalent radical of a heteroalkyl group in which heteroatoms may occupy one or both ends of the chain, including but not limited to -CH2-CH2-O-CH2-, -CH2-CH2-NH-CH2-, -CH2-CH2-N(CH3)-CH2-, -CH2-S-CH2-CH2-, -CH2-CH2-O-, -O-CH2-CH2-O-, -CH2-CH2-N-, -N-CH2-CH2-N-.

[0645] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which can be combined with other groups. Monocyclic cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, a 3-8-membered cycloalkyl group. More preferably, a 3-6-membered cycloalkyl group. More preferably, a 3-5-membered cycloalkyl group. Polycyclic cyclic hydrocarbon groups include linked rings, spiro rings, condensed rings, or bridged ring cyclic hydrocarbon groups, including but not limited to the following groups:

[0646]

[0647] "Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated π electron system and can be combined with other groups. Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc. Preferably, 3-8-membered cycloalkenyls. More preferably, 3-6-membered cycloalkenyls. More preferably, 5-6-membered cycloalkenyls. Polycyclic cycloalkenyls include linked rings, spiro rings, condensed rings or bridged ring cycloalkenyls. Including but not limited to the following groups:

[0648]

[0649] The cycloalkyl or cycloalkenyl group may be fused with an aryl group, a heteroaryl group or a heterocyclic group, including but not limited to a tetrahydronaphthyl group, a benzocycloheptyl group and the like.

[0650] "Alkenyl" refers to a linear, branched or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to ethenyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably C2-6 More preferably C 2-4 Alkenyl.

[0651] "Heteroalkenyl" refers to an alkenyl group in which the carbon atoms are replaced by one or more heteroatoms selected from O, N, S, S(=O), S(=O)2 or Si, including but not limited to -CH=CH-O-CH3, -CH=CH-NH-CH3, -CH ＝ CH-N(CH3)-CH3, -CH2-S-CH=CH2.

[0652] "Heteroalkenylene" refers to a divalent radical of a heteroalkenyl group in which heteroatoms may occupy one or both ends of the chain, including but not limited to -CH=CH-O-CH2-, -CH=CH-NH-CH2-, -CH=CH-N(CH3)-CH2-, -CH2-S-CH=CH-, -CH=CH-O-, -O-CH=CH-O-, -CH=CH-N-, and -N-CH=CH-N-.

[0653] "Alkynyl" refers to a straight chain, branched or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. 2-6 More preferably C 2-4 Alkynyl.

[0654] "Alkylene" refers to a straight or branched, divalent saturated hydrocarbon group, i.e., one hydrogen atom of the alkyl group is further substituted, including but not limited to "methylene" refers to -CH2-, "ethylene" refers to -CH2CH2-, "propylene" refers to -CH2CH2CH2-, and "butylene" refers to -CH2CH2CH2CH2- or -CH2CH(CH3)CH2-.

[0655] "Alkenylene" refers to a straight or branched, divalent alkenyl group, i.e., one hydrogen atom of the alkenyl group is further substituted, including but not limited to "vinylene" refers to -CH=CH-, "propenylene" refers to -CH=CHCH2-, "butenylene" refers to -CH=CHCH2CH2- or -CH2CH=CHCH2- or -CH=C(CH3)CH2-, etc.

[0656] "Alkynylene" refers to a straight or branched, divalent alkynyl group, i.e., one of the hydrogen atoms of the alkynyl group is further substituted, including but not limited to "ethynylene" refers to -C≡C-, "propynylene" refers to -C≡CCH2-, "butynylene" refers to -CH2C≡CCH2- or -C≡CCH2CH2-, etc.

[0657] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0658] "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms have been replaced by the same or different halogen atoms, including but not limited to -CH2Cl, -CHF2, -CH2CCl3, -CH2CHF2, -CH2CF3, perfluoroalkyl (e.g., -CF3), etc.

[0659] "Alkylamino" refers to NH3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, etc.

[0660] "Dialkylamino" refers to a group having the structure N(C 1-6 The invention also includes but is not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino and the like.

[0661] "Aryl" refers to a monocyclic or polycyclic carbon ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, indenyl. Preferably, it is a 6-10 membered monocyclic or bicyclic aromatic group. More preferably, it is phenyl or naphthyl. Most preferably, it is phenyl.

[0662] "Heterocyclyl" refers to a group of a 4-12 membered non-aromatic monocyclic or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings with only single bonds and unsaturated rings with at least one double bond (C=C, C=N or N=N), but not forming a completely conjugated π electron system. The heteroatoms are independently selected from N, O, S, nitrogen oxide (NO), sulfoxide, S(O)(=NH) and sulfone. Polycyclic systems include fused, bridged or spirocyclic systems. Examples of monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl (azetidinyl), oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc. Preferred are 4-7 membered heterocyclic groups. More preferred are 4-6 membered heterocyclic groups. Examples of polycyclic heterocyclyl moieties include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2 .1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, etc. Examples of unsaturated heterocyclic moieties include, but are not limited to:

[0663]

[0664] The heterocyclic group may be fused to an aryl group, a heteroaryl group or a cycloalkyl group, including but not limited to the following groups:

[0665]

[0666] The heterocyclic group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: deuterium atoms, halogen, CN, nitro, hydroxyl, azido, C 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0667] "Heteroaryl" refers to a substituted or unsubstituted 5- or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or biheteroaromatic ring system, containing 1-4 heteroatoms independently selected from N, O, or S, and the remaining ring atoms are carbon atoms. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl, or benzothiazolyl.

[0668] The heteroaryl group may be fused to an aryl group, a heterocyclic group or a cycloalkyl group, including but not limited to the following groups:

[0669]

[0670] The heteroaryl group is optionally substituted or unsubstituted, and the substituted substituents are preferably one or more of the following groups: deuterium atoms, halogens, CN, nitro, hydroxyl, azido, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6 heteroalkenyl, 3-12 membered saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, deuterated C 1-10 Alkyl, deuterated C 1-10 Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, oxo (=O).

[0671] "Alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy and other similar groups. Preferably C 1-8 Alkoxy. More preferably C 1-6 Alkoxy. More preferably C 1-4 Alkoxy.

[0672] "Cycloalkoxy" refers to an -O-cycloalkyl group in which the cycloalkyl group is as defined above. Preferably C 3-8 Cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and other similar groups.

[0673] "Heterocyclyloxy" refers to -O-heterocyclyl, wherein the heterocyclyl group is as described above, including but not limited to azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxhexyloxy, piperidinyloxy and other similar groups.

[0674] "Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts, which retain the biological effectiveness and properties of the compound of formula I, and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid. The organic acids are such as acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, magnesium salts. The organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc. Chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds.

[0675] "Prodrug molecule" refers to a prodrug that can be converted into a compound of the present invention and a pharmaceutically acceptable salt thereof in vivo.

[0676] "N-oxide" refers to a compound containing an amine functional group or a heteroaryl compound containing a nitrogen atom, which can be formed by oxidizing one or more nitrogen atoms. + The compound is preferably an N-oxide of a tertiary amine or an N-oxide of a heteroaryl group containing N.

[0677] "Hydrate" refers to an association formed with a certain amount of water.

[0678] "Solvate" refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and the like.

[0679] "Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutically acceptable carriers, excipients or diluents. The purpose of a pharmaceutical composition is to facilitate the process of administration to an animal. A pharmaceutical composition may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH regulators and buffers, toxicity regulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

[0680] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which participates in loading or delivering the compounds of the present invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient or other material that is not excessively toxic or has side effects and can be used to contact animal tissues.

[0681] Some pharmaceutically acceptable carrier materials include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) (11) glycols, such as propylene glycol; (12) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) lipids, such as ethyl oleate and ethyl laurate; (14) agarose; (15) buffers, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) sterile pyrogen-free water; (18) Ringer's solution; (19) alcohols, such as ethanol and propanol; (20) phosphate buffer; (21) other non-toxic and compatible substances in pharmaceutical dosage forms, such as acetone.

[0682] Each pharmaceutically acceptable carrier should be compatible with other components, for example, forming a preparation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs of organisms, and with a reasonable benefit-risk ratio.

[0683] The pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The preparation methods and processes of pharmaceutical compositions are well known and can be prepared according to conventional processes, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). DETAILED DESCRIPTION

[0684] The first group of preparation examples: Preparation of intermediates A1-A9

[0685] Intermediate A1. Preparation of 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinoline

[0686]

[0687] Step 1: Pd(PPh3)4 (8.2g, 7.1mmol) and bis-pinacol borate (21.7g, 85.6mmol) were dissolved in toluene (50mL), nitrogen was replaced, but-3-yn-1-ol (5.0g, 71.3mmol) and acetic acid (3.6mL, 62.8mmol) were added, the reaction solution was pre-stirred at room temperature for 5min, and then heated to 80℃ and stirred for 0.5h in microwave. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-15%) as the eluent gradient elution to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-ene-1-ol (colorless oil, 12g, 84.9%). MS (ESI + )m / z=199.2[M+H] + .

[0688] Step 2: Dissolve 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (12.0 g, 60.6 mmol) in dichloromethane (100 mL), replace nitrogen, add imidazole (8.2 g, 121.2 mmol) and TBSCl (13.7 g, 90.9 mmol) in turn, and stir at room temperature for 16 h. After the reaction is complete, water (50 mL) is added to the reaction solution to quench the reaction, and the mixture is extracted with dichloromethane (50 mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-15%) as an eluent by gradient elution to obtain tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (yellow oil, 12 g, 63.4%). MS (ESI + )m / z=313.2[M+H] + .

[0689] Step 3: Dissolve tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (6.0 g, 19.2 mmol), 8-bromo-3-chloro-5-iodoisoquinoline (8.5 g, 23.1 mmol), Pd(dppf)Cl2 (1.4 g, 1.9 mmol) and potassium carbonate (8.0 g, 57.6 mmol) in 1,4-dioxane (60 mL) and water (6 mL), replace nitrogen, heat to 60 ° C and stir for 5 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using ethyl acetate / petroleum ether (0-10%) as an eluent in a gradient elution to obtain 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-chloroisoquinoline (yellow oil, 3 g, 36.6%). MS (ESI + )m / z=428.0[M+H] + .

[0690] Step 4: Dissolve 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)but-1-en-2-yl)-3-chloroisoquinoline (3.0 g, 7.0 mmol) in ethyl acetate (150 mL), slowly add platinum dioxide (638.4 mg, 2.8 mmol), replace hydrogen, and stir at room temperature for 8 h. After the reaction is complete, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)but-2-yl)-3-chloroisoquinoline (yellow solid, 2.5 g, crude product). MS (ESI + )m / z=430.0[M+H] + .

[0691] Intermediate A2. Preparation of 8-bromo-5-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-chloroisoquinoline

[0692]

[0693] 8-Bromo-3-chloro-5-iodoisoquinoline and tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane were used as raw materials to prepare 8-Bromo-5-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-chloroisoquinoline (Intermediate A2) according to the third and fourth steps of the synthesis of Intermediate A1. MS (ESI + )m / z=416.1[M+H] + .

[0694] Intermediate A3. Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine

[0695]

[0696] Step 1: Under nitrogen protection, 5-bromo-3-chloroisoquinoline (1.0 g, 4.1 mmol), N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (1.2 g, 6.2 mmol), cesium carbonate (4.1 g, 12.2 mmol), 1,4-dioxane (10 mL), Xphos Pd G3 (0.4 g, 0.4 mmol) and Xphos (0.2 g, 0.41 mmol) were added to a 40 mL single-mouth bottle in sequence, and the mixture was heated to 90 °C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (30 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to obtain N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-N-methylisoquinolin-5-amine (white solid, 700 mg, 48.3%). MS (ESI + )m / z=351.2[M+H] + .

[0697] Step 2: Under nitrogen protection, dissolve N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-N-methylisoquinolin-5-amine (700 mg, 2.0 mmol) in N,N-dimethylformamide (7 mL) in a 40 mL single-mouth bottle, add N-iodosuccinimide (899.9 mg, 4.0 mmol), heat to 60 ° C and stir for 1 h. After the reaction is complete, cool to room temperature, add water (10 mL) to quench the reaction, extract the mixed solution with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (15 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to obtain N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine (white solid, 700 mg, 73.5%). MS (ESI + )m / z=477.1[M+H] + .

[0698] Intermediate A4. Preparation of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine

[0699]

[0700] Step 1: Dissolve 3-(methylamino)propan-1-ol (5.0 g, 56.1 mmol) in dichloromethane (100 mL) in a 250 mL reaction bottle, then add imidazole (11.5 g, 168.3 mmol), cool to 0 ° C, add TBSCl (12.6 g, 84.2 mmol) under stirring, and stir the reaction solution at room temperature for 1 h. After the reaction is complete, add water (50 mL) to quench the reaction. The mixed solution is extracted with dichloromethane (50 mL × 3), the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-30%) as the eluent to obtain 3-((tert-butyldimethylsilyl)oxy)-N-methyl-1-propylamine (yellow oil, 5.5 g, 49%). MS (ESI + )m / z=204[M+H] + .

[0701] Step 2 and Step 3: Using 3-((tert-butyldimethylsilyl)oxy)-N-methyl-1-propylamine and 3-chloro-5-iodoisoquinoline as raw materials, prepare N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine (Intermediate A4) according to the method for synthesizing Intermediate A3.

[0702] Intermediate A5. Preparation of 8-bromo-3-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinoline

[0703]

[0704] Under nitrogen protection, 8-bromo-3-chloro-5-iodoisoquinoline (2.0 g, 5.5 mmol) was dissolved in NN-dimethylformamide (20 mL) in a 40 mL reaction bottle, and 2-(allyloxy)tetrahydro-2H-pyran (3.1 g, 21.8 mmol), Pd2(dba)3 (0.5 g, 0.55 mmol), triphenylphosphine (2.9 g, 10.9 mmol), tetramethylammonium chloride (1.2 g, 5.4 mmol) and potassium phosphate (3.5 g, 16.4 mmol) were added in sequence. The temperature was raised to 80 °C and stirred for 4 h. After the reaction was complete, the temperature was cooled to room temperature, and water (30 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-8%) as eluent to obtain 8-bromo-3-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinoline (white solid, 800 mg, 38.2%). MS (ESI + )m / z=384.1[M+H]+ .

[0705] Intermediate A6. Preparation of 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-propanol

[0706]

[0707] Step 1: In a 100 mL reaction bottle, 8-bromo-3-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinoline (Intermediate A5, 5.0 g, 13.1 mmol) was dissolved in methanol (50 mL), and then p-toluenesulfonic acid (11.23 g, 65.3 mmol) was added, and the temperature was raised to 60 ° C and stirred for 1 h. After the reaction was complete, the temperature was lowered to room temperature and concentrated under reduced pressure. The obtained residue was separated and purified by preparative liquid chromatography with water / acetonitrile (0-30%) as the eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (white solid, 3.7 g, 95.1%). MS (ESI + )m / z=300.0[M+H] + .

[0708] Step 2: Dissolve 3-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (1.0 g, 3.3 mmol) in dichloromethane (10 mL) in a 100 mL reaction bottle, add Dess-Martin (2.8 g, 6.7 mmol) under ice bath, and stir the reaction solution at room temperature for 3 h. After the reaction is complete, add saturated brine (30 mL), extract the mixture with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with methanol / dichloromethane (0-20%) as eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)propanal (yellow oil, 880 mg, 88%). MS (ESI + )m / z=298.1[M+H] + .

[0709] Step 3: Dissolve 3-(8-bromo-3-chloroisoquinolin-5-yl)propanal (880 mg, 3.0 mmol) in tetrahydrofuran (5 mL) in a 100 mL reaction bottle, add L-proline (0.85 g, 7.4 mmol) and N-fluorobisbenzenesulfonamide (1.9 g, 5.9 mmol) in turn, and stir the reaction solution at room temperature for 2 h. After the reaction is complete, add potassium bicarbonate aqueous solution (5 mL) to quench the reaction, extract the mixed solution with dichloromethane (15 mL × 3), combine the organic phases, dry them over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-60%) as the eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoropropanal (yellow solid, 360 mg, 36.6%). MS (ESI + )m / z=334.0[M+H] + .

[0710] Step 4: Dissolve 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoropropanal (360 mg, 1.1 mmol) in methanol (20 mL) in a 100 mL reaction bottle, cool to 0 ° C, slowly add sodium borohydride (86.7 mg, 2.2 mmol), and stir the reaction solution at room temperature for 4 h. After the reaction is complete, add water (30 mL) to quench the reaction, extract the mixed solution with dichloromethane (100 mL × 3), wash the combined organic phases with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by preparative liquid chromatography with acetonitrile / 0.1% sodium bicarbonate aqueous solution (0-25%) as the eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-propanol (yellow solid, 200 mg, 55.6%). MS (ESI + )m / z=336.1[M+H] + .

[0711] Intermediate A7. Preparation of 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-butanol

[0712]

[0713] Step 1: In a 100 mL reaction bottle, 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinoline (Intermediate A1, 2.0 g, 4.7 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and TBAF (4.7 mL, 1 M THF solution, 4.7 mmol) was added with stirring. After the addition was completed, the reaction solution was stirred at room temperature for 1 h. After the reaction was complete, water (100 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-60%) as eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol (white solid, 1.2 g, 81%).

[0714] Step 2, Step 3, Step 4: Using 3-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol as raw material, prepare 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-butanol (Intermediate A7) according to the method of Step 2, Step 3 and Step 4 of the synthetic intermediate A6. MS (ESI + )m / z=347.6[M+H] + .

[0715] Intermediate A8. Preparation of 4-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol

[0716]

[0717] Step 1: Dissolve 3-chloroisoquinoline (100.0 g, 0.61 mol) in trifluoromethanesulfonic acid (2 L), cool to -10 ° C, slowly add N-iodosuccinimide (151.3 g, 0.67 mol), and stir at -10 ° C for 1 h. After the reaction is complete, slowly add ice water (10 L) to the reaction solution, filter, collect the filter cake and dissolve it with ethyl acetate (800 mL), adjust the pH to 7 with ammonia water, extract the resulting mixture with ethyl acetate (800 mL × 2), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-20%) as the eluent gradient elution to obtain 3-chloro-5-iodoisoquinoline (light yellow solid, 150 g, 84.7%). MS (ESI + )m / z=290.0[M+H] + .

[0718] Step 2: Dissolve 3-chloro-5-iodoisoquinoline (150.0 g, 0.52 mol) in concentrated sulfuric acid (2 L) at 0 ° C, slowly add N-bromosuccinimide (92.2 g, 0.52 mol) in batches, and stir at 0 ° C for 0.5 h. After the reaction is complete, slowly add ice water (4 L) to the reaction solution, filter, collect the filter cake and dissolve it in ethyl acetate (5 L), dry it with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-20%) as the eluent gradient elution to obtain 8-bromo-3-chloro-5-iodoisoquinoline (light yellow solid, 90 g, 47.4%). MS (ESI + )m / z=369.9[M+H] + .

[0719] Step 3: Under nitrogen protection, 8-bromo-3-chloro-5-iodoisoquinoline (3.0 g, 8.14 mmol) was dissolved in DMF (250 mL), and but-3-en-1-ol (2.4 g, 33.4 mmol), tetramethylammonium hydroxide aqueous solution (2.6 g, 28.5 mmol), Pd2(dba)3 (175 mg, 0.19 mmol), triphenylphosphine (750.8 mg, 2.86 mmol) and potassium phosphate (6.1 g, 28.62 mmol) were added in sequence, and the temperature was raised to 80 ° C and stirred for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (40 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (250 mL×3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-35%) as the eluent and gradient elution to obtain 4-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol (white solid, 420 mg, 16.3%).

[0720] Intermediate A9. Preparation of 8-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloroisoquinoline

[0721]

[0722] Step 1: Using 8-bromo-3-chloro-5-iodoisoquinoline (4.0 g, 10.86 mmol) and 3-(tert-butyldimethylsilyloxy)propen-1-yl-boronic acid pinacol ester (3.90 g, 13.03 mmol) as raw materials, 8-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-chloroisoquinoline (yellow solid, 800 mg, 17.8%) was prepared according to the method of the third step of the synthesis of intermediate A1. MS (ESI + )m / z=412.1[M+H] + .

[0723] Step 2: Under nitrogen protection, 8-bromo-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-chloroisoquinoline (800.0 mg, 1.94 mmol) was dissolved in ethyl acetate (50 mL), rhodium carbon (997.1 mg, 9.69 mmol) was added, hydrogen was replaced, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1-10%) as the eluent to obtain 8-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloroisoquinoline (white solid, 200 mg, crude product). MS (ESI + )m / z=300.1[M-TBS+H] + The second group of preparation examples: Preparation of intermediates B1-B11

[0724] Intermediate B1. Preparation of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0725]

[0726] Step 1: Dissolve 2-chloropyrimidin-4-amine (20.0 g, 154.4 mmol) in tetrahydrofuran (200 mL), replace nitrogen, cool to 0 ° C, add DMAP (1.9 g, 15.4 mmol), triethylamine (45.9 g, 453.9 mmol) and Boc2O (100.0 g, 458.5 mmol) in sequence, and stir at room temperature for 16 h. After the reaction is complete, add water (100 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (100 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to obtain tert-butyl (tert-butyloxycarbonyl) (2-chloropyrimidin-4-yl) carbamate (white solid, 50 g, 98.2%). MS (ESI + )m / z=330.0[M+H] + .

[0727] Step 2: Dissolve 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (10.0 g, 0.033 mol), tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (53.7 g, 0.16 mol), bis-pinacol borate (41.3 g, 0.16 mol), Pd(Amphos)2Cl2 (4.6 g, 6.5 mmol) and sodium carbonate (17.2 g, 0.16 mol) in acetonitrile (100 mL) and water (10 mL), replace nitrogen, heat to 100 ° C and stir for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high pressure preparative liquid chromatography (mobile phase: acetonitrile / water (0.1% ammonia water)) to obtain tert-butyl (tert-butyloxycarbonyl)(2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (white solid, 3.4 g, 20.0%). MS (ESI + )m / z=522.3[M+H] + .

[0728] Step 3: Dissolve tert-butyl (tert-butoxycarbonyl)(2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (3.4 g, 6.5 mmol) in methanol (40 mL), slowly add an aqueous solution (40 mL) of sodium hydroxide (521.4 mg, 13.0 mmol), replace nitrogen, and heat to 80 ° C and stir for 24 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (white solid, 2 g, 95.5%). MS (ESI + )m / z=322.0[M+H] + .

[0729] Intermediate B2. Preparation of 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)pyrimidin-4-amine

[0730]

[0731] Step 1: Dissolve 3-bromo-2-methylpyridine (25.0 g, 145.33 mmol) in dichloromethane (200 mL) in a 500 mL single-mouth bottle at 0°C, and slowly add m-chloroperbenzoic acid (35.0 g, 202.83 mmol). The reaction mixture was stirred at 30°C overnight. After the reaction was complete, the reaction solution was slowly poured into ice water, adjusted to pH = 10 with saturated sodium sulfite solution, extracted with ethyl acetate (1.2 L × 3), combined the organic phases, 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 (0-10%) as the eluent to obtain 3-bromo-2-methylpyridine 1-oxide (white solid, 25.0 g, 91.5%). MS (ESI + )m / z=188.0[M+H] + .

[0732] Step 2: Dissolve 3-bromo-2-methylpyridine 1-oxide (25.0 g, 132.96 mmol) in concentrated sulfuric acid (200 mL) in a 500 mL single-mouth bottle at 0 ° C, slowly add concentrated nitric acid (51.8 g, 534.34 mmol), heat to 90 ° C and stir overnight. After the reaction is complete, cool the reaction solution to room temperature, slowly pour it into ice water to quench the reaction, add saturated sodium carbonate solution to adjust pH to 9, and extract with ethyl acetate (1.2 L × 3). Combine the organic phases, wash with saturated brine (500 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain 3-bromo-2-methyl-4-nitropyridine 1-oxide (yellow solid, 15.2 g, 49.1%). MS (ESI + )m / z=232.9[M+H] + .

[0733] Step 3: At room temperature, 3-bromo-2-methyl-4-nitropyridine 1-oxide (15.2 g, 65.23 mmol) was dissolved in acetonitrile (150 mL) in a 500 mL single-mouth bottle, phosphorus oxychloride (50.0 g, 326.11 mmol) was slowly added dropwise, and the temperature was raised to 80 ° C and stirred overnight. After the reaction was complete, the reaction solution was cooled to 0 ° C, water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (800 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with methanol / dichloromethane (0-20%) as the eluent to obtain 3-bromo-4-chloro-2-methylpyridine 1-oxide (yellow solid, 11.6 g, 80.1%). MS (ESI + )m / z=224.0[M+H] + .

[0734] Step 4: At room temperature, add 3-bromo-4-chloro-2-methylpyridine 1-oxide (11.5 g, 51.69 mmol), ethanol (120 mL), water (40 mL), ammonium chloride (27.8 g, 519.72 mmol) and iron powder (14.6 g, 261.44 mmol) to a 500 mL single-mouth bottle in sequence, and heat to 80 ° C and stir for 2 h. After the reaction is complete, cool to room temperature, filter, wash the filter residue with dichloromethane, add water (100 mL) to dilute the filtrate, and extract with dichloromethane (800 mL × 3). Combine the organic phases and dry with anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with methanol / dichloromethane (0-20%) as the eluent to obtain 3-bromo-4-chloro-2-methylpyridine 4 (5.4 g, 50.6%) as a yellow oil. MS (ESI + )m / z=206.0[M+H] + .

[0735] Step 5: At 0°C, sodium hydride (1.2 g, 30.00 mmol, 60%) and N,N-dimethylformamide (80 mL) were added to a 250 mL single-mouth bottle in sequence, 4-methoxybenzyl alcohol (4.0 g, 28.77 mmol) was added in batches, and then 3-bromo-4-chloro-2-methylpyridine (5.4 g, 26.15 mmol) was added, and the temperature was raised to 80°C and stirred for 2 h. After the reaction was complete, the temperature was lowered to room temperature, and water (50 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to give 3-bromo-4-((4-methoxybenzyl)oxy)-2-methylpyridine (white solid, 5.8 g, crude product). MS (ESI + )m / z=308.0[M+H] + .

[0736] Step 6: At room temperature, 3-bromo-4-((4-methoxybenzyl)oxy)-2-methylpyridine (5.8 g, 18.82 mmol) was dissolved in 1,4-dioxane (120 mL) in a 250 mL single-mouth bottle, and then diboric acid pinacol ester (33.6 g, 132.32 mmol), potassium acetate (5.6 g, 57.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1.5 g, 1.84 mmol) were added in sequence. Under nitrogen protection, the temperature was raised to 100 ° C and stirred for 2 days. After the reaction was complete, the temperature was lowered to room temperature, water (100 mL) was added to dilute, and the mixture was extracted with ethyl acetate (500 mL×3). The organic phases were combined, 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 using methanol / dichloromethane (0-20%) as eluent to obtain 4-((4-methoxybenzyl)oxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (brown oil, 3.7 g, 55.4%). MS (ESI + )m / z=356.2[M+H] + .

[0737] Step 7: At room temperature, add 4-((4-methoxybenzyl)oxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.7 g, 10.42 mmol), 1,4-dioxane (70 mL) and water (7 mL), 2-bromopyrimidin-4-amine (1.2 g, 6.90 mmol), potassium carbonate (2.9 g, 20.84 mmol) and tetrakis(triphenylphosphine)palladium (0.8 g, 0.69 mmol) to a 250 mL single-mouth bottle. Under nitrogen protection, heat to 100 ° C and stir overnight. After the reaction is complete, cool to room temperature, add water (100 mL) to dilute, extract with ethyl acetate (500 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as eluent to obtain 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)pyrimidin-4-amine (yellow solid, 270.0 mg, 12.1%). MS (ESI + )m / z=323.1[M+H] + .

[0738] Preparation of Intermediate B3.2-(4-methoxypyridin-3-yl)pyrimidin-4-amine

[0739]

[0740] 2-(4-methoxypyridin-3-yl)pyrimidin-4-amine (Intermediate B3) was prepared using (4-methoxypyridin-3-yl)boronic acid and 2-bromopyrimidin-4-amine as raw materials according to the seventh step of the synthesis of intermediate B2. MS (ESI + )m / z=203.1[M+H] + .

[0741] Intermediate B4. Preparation of 2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine

[0742]

[0743] Step 1: Dissolve 3-bromopyridin-4-ol (50 g, 289 mmol) in acetonitrile (500 mL) in a 1000 mL three-necked round-bottom flask, add potassium carbonate (80 g, 581 mmol), then add benzyl bromide (54.4 g, 318 mmol) dropwise, and stir the reaction solution at room temperature for 12 h. After the reaction is complete, add water (100 mL), extract the mixture with ethyl acetate (300 mL × 2), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with methanol / dichloromethane (0-5%) as the eluent to obtain 4-benzyloxy-3-bromopyridine (white solid, 60 g, 78.9%). MS (ESI + )m / z=264.0[M+H] + .

[0744] Step 2: Under nitrogen protection, 4-benzyloxy-3-bromopyridine (10 g, 38.0 mmol) was dissolved in 1,4-dioxane (500 mL) in a 1000 mL three-necked round-bottom flask, and Pd(dppf)Cl2 (3.11 g, 3.8 mmol), potassium acetate (11.2 g, 114.1 mmol) and bis-pinacol borate (19.3 mg, 76.1 mmol) were added in sequence, and the temperature was raised to 110°C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, and the reaction mixture was directly separated and purified by preparative liquid chromatography using acetonitrile / water (0-5%) as the eluent to obtain (4-(benzyloxy)pyridin-3-yl)boronic acid (yellow solid, 6 g, 68.6%). MS (ESI + )m / z=230.1[M+H] + .

[0745] Step 3: Under nitrogen protection, in a 1000mL three-necked round-bottom flask, (4-(benzyloxy)pyridin-3-yl)boric acid (6.0g, 26.2mmol) was dissolved in a mixture of 1,4-dioxane and water (550mL, 10 / 1, v / v), and (2-chloropyrimidin-4-yl)(tert-butyloxycarbonyl)carbamate (12.9g, 39.3mmol), Pd(dppf)Cl2 (2.1g, 2.6mmol) and potassium carbonate (10.9g, 78.6mmol) were added in sequence, and the temperature was raised to 90°C and stirred for 1h. After the reaction was complete, the temperature was lowered to room temperature, water (100mL) was added, and the mixture was extracted with ethyl acetate (500mL×3), the organic phases were combined, washed with saturated brine (50mL), 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 using methanol / dichloromethane (0-5%) as eluent to obtain tert-butyl (2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (yellow oil, 6.0 g, 48%). MS (ESI + )m / z=379.2[M-100+H] + .

[0746] Step 4: Dissolve tert-butyl (2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (6.0 g, 12.6 mmol) in dichloromethane (50 mL) in a 100 mL three-necked round-bottom flask, add trifluoroacetic acid (10 mL), and stir the reaction solution at room temperature for 1 h. After the reaction is complete, concentrate under reduced pressure to obtain 2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine (brown solid, 4.0 g, crude product). MS (ESI + )m / z=279.2[M+H] + .

[0747] Preparation of Intermediate B5.2-(4-fluoropyridin-3-yl)pyrimidin-4-amine

[0748]

[0749] Step 1: Under nitrogen protection, 3-bromo-4-fluoropyridine (1g, 5.7mmol) was dissolved in 1,4-dioxane (20mL) in a 100mL reaction bottle, and bis-pinacol borate (2.8g, 11.0mmol), Pd(dppf)Cl2 (415mg, 0.57mmol) and potassium acetate (1.7g, 17.3mmol) were added in sequence, and the temperature was raised to 90℃ and stirred for 5h. After the reaction was complete, the temperature was lowered to room temperature, and water (5mL) was added to quench the reaction, and the reaction was concentrated under reduced pressure to obtain 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (black oil, 1g, 78%). The crude product was used directly in the next step without purification.

[0750] Step 2: Under nitrogen protection, 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (950 mg, 4.3 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 mL, 9 / 1, v / v) in a 100 mL reaction bottle, and 2-chloropyrimidine-4-amine (1.1 g, 8.5 mmol), Pd(dppf)Cl2 (312 mg, 0.43 mmol) and potassium carbonate (1.8 g, 13.0 mmol) were added in sequence, and the temperature was raised to 100 ° C and stirred for 1 h. After the reaction was complete, the temperature was lowered to room temperature, and water (20 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-31%) as eluent to give 2-(4-fluoropyridin-3-yl)pyrimidin-4-amine (white solid, 310 mg, 31%). MS (ESI + )m / z=191.1[M+H] + .

[0751] Intermediate B6. Preparation of 4-(4-aminopyrimidin-2-yl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0752]

[0753] Step 1: Dissolve 2,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (50.0 g, 446.4 mmol) in dichloromethane (1500 mL) in a 2000 mL round-bottom flask, then add potassium carbonate (308.0 g, 2232.1 mmol), slowly drop 2-(trimethylsilyl)ethoxymethyl chloride (111.2 g, 669.6 mmol) under ice bath, and stir at room temperature for 16 h. After the reaction is complete, add water (500 mL), extract the mixture with dichloromethane (1000 mL × 3), combine the organic phases, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-5%) as eluent to obtain 2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow oil, 50 g, 46.3%). MS (ESI + )m / z=243.2[M+H] + .

[0754] Step 2: Dissolve 2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (50.0 g, 206.6 mmol) in chloroform (1000 mL) in a 100 mL round-bottom flask, cool to 0°C, add N-bromosuccinimide (43.9 g, 247.9 mmol) in batches, stir at 25°C for 2 h. After the reaction is complete, add saturated sodium thiosulfate (1000 mL) to quench the reaction, extract the mixed solution with dichloromethane (500 mL×3), wash the combined organic phases with saturated brine (1000 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-2%) as eluent to obtain 4-bromo-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 40 g, 60.3%). MS (ESI + )m / z=321.1[M+H] + .

[0755] Step 3 and Step 4: Using 4-bromo-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one, tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate and tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate as raw materials, 4-(4-aminopyrimidin-2-yl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (Intermediate B6) was prepared according to the method of Step 2 and Step 3 of Synthesis of Intermediate B1. MS (ESI + )m / z=336.3[M+H] + .

[0756] Preparation of Intermediate B7.2-(4-methoxypyridin-3-yl)-6-methylpyrimidin-4-amine

[0757]

[0758] Step 1: Dissolve 2-chloro-6-methylpyrimidin-4-amine (24.0 g, 0.17 mol) in THF (300 mL), add DMAP (1.0 g, 8.36 mmol) and Boc2O (73.0 g, 0.33 mol) in turn, and stir at room temperature for 4 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure, water (200 mL) is added to the obtained residue, and the mixed solution is extracted with ethyl acetate (200 mL×3), the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (10%) as the eluent to obtain tert-butyl (tert-butoxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)carbamate (yellow solid, 50 g, 87.0%). MS (ESI + )m / z=344.2[M+H] + .

[0759] Step 2 and Step 3: Using (tert-butyloxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)carbamic acid tert-butyl ester and 4-methoxypyridine-3-boronic acid pinacol ester as raw materials, 2-(4-methoxypyridin-3-yl)-6-methylpyrimidin-4-amine (Intermediate B7, light brown solid) was prepared according to the method of Step 3 and Step 4 of the synthetic intermediate B4. MS (ESI + )m / z=217.2[M+H] + .

[0760] Preparation of intermediate B8.6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-amine trifluoroacetate

[0761]

[0762] Step 1: Using 2,6-dichloropyrimidin-4-amine and Boc2O as raw materials, prepare (tert-butyloxycarbonyl)(2,6-dichloropyrimidin-4-yl)carbamic acid tert-butyl ester (white solid) according to the method of the first step of the synthesis of intermediate B7. MS (ESI + )m / z=364.0[M+H] + .

[0763] Step 2: Under nitrogen protection, dissolve tert-butyl (tert-butoxycarbonyl)(2,6-dichloropyrimidin-4-yl)carbamate (50.0 g, 137.3 mmol) in a 1,4-dioxane / water mixture (550 mL v / v, 10 / 1), and add vinylboronic acid pinacol ester (23.3 g, 151.1 mmol), Pd(dppf)Cl2 (10.0 g, 13.7 mmol) and K2CO3 (38.0 g, 275.0 mmol) in sequence, and heat to 100 °C and stir for 1 h. After the reaction is complete, cool to room temperature, add water (500 mL) to the reaction solution, extract the mixture with ethyl acetate (5000 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-20%) as the eluent gradient elution to obtain (tert-butyloxycarbonyl)(2-chloro-6-vinylpyrimidin-4-yl)carbamic acid tert-butyl ester (white oil, 27 g, 55.3%). MS (ESI + )m / z=356.1[M+H] + .

[0764] Step 3: Under nitrogen protection, dissolve (tert-butyloxycarbonyl)(2-chloro-6-vinylpyrimidin-4-yl)carbamate (23.0 g, 64.64 mmol) in ethyl acetate (230 mL), add platinum dioxide (5.9 g, 25.86 mmol), replace hydrogen, and stir at room temperature for 4 hours. After the reaction is complete, the reaction solution is filtered through diatomaceous earth, the filter residue is washed with ethyl acetate (200 mL), and the filtrate is concentrated under reduced pressure to obtain (tert-butyloxycarbonyl)(2-chloro-6-ethylpyrimidin-4-yl)carbamate (black solid, 22.8 g, 98.6%). MS (ESI + )m / z=358.2[M+H] + .

[0765] Step 4: Under nitrogen protection, tert-butyl (tert-butoxycarbonyl)(2-chloro-6-ethylpyrimidin-4-yl)carbamate (2.0 g, 5.59 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 44 mL), and Pd(dppf)Cl2 (409.0 mg, 0.56 mmol), Cs2CO3 (3.6 g, 11.18 mmol) and 4-methoxypyridine-3-boronic acid pinacol ester (1.4 g, 6.15 mmol) were added in sequence, and the temperature was raised to 100 °C and stirred for 1 h. After the reaction is complete, cool to room temperature, add water (100 mL) to the reaction solution, extract the mixture with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (20%) as eluent to obtain tert-butyl (tert-butoxycarbonyl)(6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)carbamate (colorless oil, 1.7 g, 70.6%). MS (ESI + )m / z=431.2[M+H] + .

[0766] Step 5: Using (tert-butyloxycarbonyl)(6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)carbamic acid tert-butyl ester (1.7 g, 3.95 mmol) as raw material, prepare 6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-amine trifluoroacetate (yellow solid, 1.2 g, 88.3%) according to the method of the fourth step of the synthesis of intermediate B4. MS (ESI + )m / z=231.2[M+H] + .

[0767] Intermediate B9. Preparation of 4-(4-amino-6-cyclopropylpyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0768]

[0769] Step 1: Dissolve tert-butyl (tert-butoxycarbonyl)(2,6-dichloropyrimidin-4-yl)carbamate (30.0 g, 82.4 mmol) in THF (30 mL), add Fe(acac)3 (5.8 g, 16.5 mmol), cool to 0°C, add cyclopropylmagnesium bromide (23.9 g, 164.7 mmol) dropwise, and stir at room temperature for 2 h. After the reaction is complete, cool to 0°C, add water (80 mL) to the reaction solution, filter, wash the filter residue with ethyl acetate (100 mL), extract the filtrate with ethyl acetate (100 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (5%) as eluent to obtain tert-butyl (tert-butoxycarbonyl)(2-chloro-6-cyclopropylpyrimidin-4-yl)carbamate (yellow oil, 23 g, 75.5%). MS (ESI + )m / z=370.1[M+H] + .

[0770] Step 2: Using tert-butyl (tert-butoxycarbonyl)(2-chloro-6-cyclopropylpyrimidin-4-yl)carbamate (6.0 g, 16.27 mmol) and 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (2.5 g, 8.1 mmol) as raw materials, tert-butyl (tert-butoxycarbonyl)(6-cyclopropyl-2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (yellow solid, 1.9 g, 41.6%) was prepared according to the method of the second step of the synthesis of intermediate B1. MS (ESI + )m / z=462.2[M-100+H] + .

[0771] Step 3: Dissolve tert-butyl (tert-butoxycarbonyl)(6-cyclopropyl-2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (1.5 g, 2.67 mmol) in hexafluoroisopropanol (60 mL), add TFA (8.5 g, 74.77 mmol) and stir at room temperature for 12 h. After the reaction is complete, the pH is adjusted to 8 with saturated sodium bicarbonate solution, the mixed solution is extracted with ethyl acetate (50 mL × 3), the organic phases are combined and dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography with methanol / dichloromethane (1 / 10) as the eluent to obtain 4-(4-amino-6-cyclopropylpyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 865 mg, 89.6%). MS (ESI + )m / z=362.2[M+H] + .

[0772] Intermediate B10. Preparation of 4-(4-amino-6-methylpyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0773]

[0774] 4-(4-amino-6-methylpyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid) was prepared using tert-butyl (tert-butoxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)carbamate and 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as raw materials according to the second and third steps of Synthesis B1. MS (ESI + )m / z=336.2[M+H] + .

[0775] Intermediate B11. Preparation of 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-amine

[0776]

[0777] Step 1: Under nitrogen protection, 4-((4-methoxybenzyl)oxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800.0 mg, 2.39 mmol) was dissolved in a mixture of 1,4-dioxane and water (11 mL, 10 / 1, v / v), and tert-butyl tert-butyloxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)carbamate (2.3 g, 6.68 mmol), Pd(dppf)Cl2 (0.18 g, 0.23 mmol) and potassium carbonate (0.94 g, 6.77 mmol) were added in sequence, and the temperature was raised to 100 °C and stirred for 1 h. After the reaction is complete, the temperature is lowered to room temperature, saturated brine (30 mL) is added, the mixed solution is extracted with ethyl acetate (30 mL × 3), the organic phases are combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (5%-20%) as eluent to obtain tert-butyl (tert-butoxycarbonyl)(2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-yl)carbamate (yellow oil, 200 g, 16.7%). MS (ESI + )m / z=537.1[M+H] + .

[0778] Step 2: Dissolve tert-butyl (tert-butoxycarbonyl)(2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-yl)carbamate (200 mg, 0.37 mmol) in methanol (5 mL) in a 250 mL reaction bottle, add sodium hydroxide solution (5 mL, 1.5 M) dropwise, heat to 80 ° C and stir for 12 h. After the reaction is complete, cool to room temperature, extract the reaction solution with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-amine (yellow solid, 100 mg, 80%). MS (ESI + )m / z=337.2[M+H] + .

[0779] The third group of preparation examples: Preparation of intermediates C1-C8

[0780] Intermediate C1. Preparation of (2R,3S)-3-(methylsulfonylmethyl)-2-methylazetidine trifluoroacetate

[0781]

[0782] Step 1: Add (2R,3S)-1-(diphenylmethyl)-2-methylazetidine-3-ol (5g, 19.7mmol) and dichloromethane (60mL) to a 40mL single-mouth bottle, and add triethylamine (6g, 59.2mmol) and methylsulfonyl chloride (3.39g, 29.6mmol) at 0°C. Replace nitrogen and stir at room temperature for 12h. Add water (30mL) to quench the reaction, extract the mixed solution with dichloromethane (20mL×3), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain (2R,3S)-1-(diphenylmethyl)-2-methylazetidine-3-yl-methanesulfonate (light yellow oil, 5g, 76.4%). MS (ESI + )m / z=332.05[M+H] + .

[0783] Step 2: Add (2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl-methanesulfonate (5g, 15.09mmol) and N,N-dimethylformamide (60mL) to a 250mL single-mouth bottle, and add sodium hydride (1.1g, 45.3mmol) at 0℃. Replace nitrogen, stir at 0℃ for 0.5h, then add methyl 2-methanesulfonyl acetate (5.7g, 37.7mmol), heat to 80℃ and stir for 12h. After the reaction is complete, cool to room temperature, add water (10mL) to quench the reaction, extract the mixed solution with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-46%) as the eluent in a gradient elution to obtain methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-methanesulfonyl acetate (white solid, 4 g, 68.4%). MS (ESI + )m / z=388.05[M+H] + .

[0784] Step 3: Add 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-methylsulfonylacetate (4g, 10.32mmol) and N,N-dimethylformamide (40mL) to a 250mL single-mouth bottle, add lithium chloride (3.5g, 82.6mmol) under stirring, heat to 150℃ and stir for 4h, cool the reaction mixture to room temperature, add water (30mL) to quench the reaction, extract the mixed solution with ethyl acetate (20mL×3), combine the organic phases, dry them over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-52%) as the eluent gradient elution to obtain (2R,3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (off-white solid, 2g, 58.8%). MS (ESI + )m / z=330.10[M+H] + .

[0785] Step 4: Add (2R, 3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (700 mg, 2.13 mmol), methanol (10.5 mL) and trifluoroacetic acid (0.35 mL) to a 50 mL single-mouth bottle, and add palladium hydroxide (208.9 mg, 1.49 mmol) while standing. Replace the hydrogen and stir at room temperature for 12 hours. Filter the mixed solution, and concentrate the filtrate under reduced pressure to obtain (2R, 3S)-3-(methylsulfonylmethyl)-2-methylazetidine trifluoroacetate (colorless semi-oily solid, 300 mg, 86.5%). MS (ESI + )m / z=164.05[M+H] + .

[0786] Preparation of intermediate C2. N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0787]

[0788] Step 1: Under nitrogen protection, (2R, 3S)-3-amino-2-methylazetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.61 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (489.0 mg, 4.83 mmol) was added, cooled to 0°C, and methylsulfonyl chloride (184.5 mg, 1.61 mmol) was slowly added dropwise under stirring, and the temperature was raised to room temperature and stirred for 1 hour. After LCMS monitoring, the reaction was completed and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 1) as the eluent to obtain (2R, 3S)-2-methyl-3-(methylsulfonamido)azetidine-1-carboxylic acid tert-butyl ester (white solid, 300 mg, 70.5%). MS (ESI + )m / z=165.10[M-100+H] + .

[0789] Step 2: Dissolve (2R,3S)-2-methyl-3-(methylsulfonamido)azetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.13 mmol) in dichloromethane / trifluoroacetic acid (3 / 1, 6 mL) in a 40 mL single-mouth bottle, stir at room temperature for 30 min, and after LCMS monitoring, concentrate under reduced pressure at low temperature to obtain N-((2R,3S)-2-methylazetidine-3-yl) methanesulfonamide (yellow oil, 400 mg, crude product). MS (ESI + )m / z=165.05[M+H] + .

[0790] Intermediate C3. Preparation of N-methyl-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0791]

[0792] Step 1: Dissolve (2R,3S)-2-methyl-3-(methylsulfonyl)azetidine-1-carboxylic acid tert-butyl ester (450 mg, 1.7 mmol) in DMF (4.79 mL), add sodium hydrogen sulfide (61.28 mg, 2.553 mmol) under stirring at 0°C, replace nitrogen, continue stirring for 0.5 h, then add iodomethane (289.96 mg, 2.042 mmol), stir at room temperature for 1 h, add water (50 mL) to quench the reaction, extract the mixed solution with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent in a gradient elution to obtain (2R,3S)-2-methyl-3-(N-methylmethanesulfonamido)azetidine-1-carboxylic acid tert-butyl ester (colorless transparent oil, 380 mg, 80.2%). MS (ESI+ )m / z=179.1[M-100+H] + .

[0793] Step 2: Using (2R,3S)-2-methyl-3-(N-methylmethanesulfonamido)azetidine-1-carboxylic acid tert-butyl ester as raw material, intermediate C3 was prepared according to the second step method of synthesizing intermediate C2. MS (ESI + )m / z=179.2[M+H] + .

[0794] Preparation of Intermediate C4.2-(Methylsulfonyl)-2,6-diazaspiro[3.3]heptane

[0795]

[0796] Step 1: Dissolve tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g, 5.0 mmol) in dichloromethane (10 mL) in a 40 mL reaction bottle, then add triethylamine (1.5 g, 15.2 mmol), and then slowly add Ms2O (1.3 g, 7.5 mmol), heat to 100 ° C and stir for 1 h. After the reaction is complete, cool to room temperature, add water (100 mL) to quench the reaction, extract the mixed solution with dichloromethane (150 mL × 3), combine the organic phases, dry them over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-60%) as the eluent to obtain tert-butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (yellow oily solid, 600 mg, 46%). MS (ESI + )m / z=277[M+H] + .

[0797] Step 2: Dissolve tert-butyl 6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg, 2.17 mmol) in dichloromethane (6 mL), cool to 0°C, slowly add trifluoroacetic acid (4 mL), stir at room temperature for 1 h, and after the reaction is complete, concentrate under reduced pressure. The residue is purified by high pressure preparative liquid chromatography (column type: XBridge BEH Prep OBDAmide Column, 19*250 mm, 5 μm; mobile phase: acetonitrile / water (10 mmol / L NH4HCO3); flow rate: 60 mL / min; gradient: 5%-95% 7 min; wavelength: 254 / 220 nm) to obtain 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (yellow oil, 250 mg, 65%). MS (ESI + )m / z=176.8[M+H] + .

[0798] Intermediate C5. Dimethyl(((2R,3S)-2-methylazetidin-3-yl)imino)-λ 6 Preparation of -sulfoxide trifluoroacetate

[0799]

[0800] Step 1: Dissolve (2R, 3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl-methanesulfonate (10.0 g, 30.17 mmol) in acetonitrile (100 mL), add Cs2CO3 (19.7 g, 60.34 mmol) and dimethylsulfonimide (4.2 g, 45.26 mmol) in turn, heat to 80 ° C and stir for 2 h. After the reaction is complete, cool to room temperature, add water (200 mL) to the reaction solution, extract the mixed solution with ethyl acetate (200 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 1) as the eluent to obtain (((2R, 3S)-1-diphenylmethyl-2-methylazetidin-3-yl)imino)dimethyl-λ 6 -sulfoxide (white solid, 6 g, 60.5%). MS (ESI + )m / z=329.1[M+H] + .

[0801] Step 2: (((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)imino)dimethyl-λ 6 -sulfone (6.0 g, 18.27 mmol) was used as the starting material, and dimethyl (((2R, 3S)-2-methylazetidin-3-yl) imino)-λ was prepared according to the method of the fourth step of the synthesis of intermediate C1. 6 -sulfoxide trifluoroacetate (white solid, 5 g, 99.1%).

[0802] Preparation of Intermediate C6. N-methyl-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride

[0803]

[0804] Step 1: Using 1-Boc-3-methylaminopyrrolidine (1.3 g, 6.49 mmol) and Ms2O (1.7 g, 9.74 mmol) as raw materials, prepare tert-butyl 3-(N-methylmethylsulfonylamino)pyrrolidine-1-carboxylate (yellow solid, 2 g, crude product) according to the method of the first step of synthesizing intermediate C4.

[0805] Step 2: Dissolve tert-butyl 3-(N-methylmethylsulfonamido)pyrrolidine-1-carboxylate (2.1 g, 7.54 mmol) in DCM (21 mL), add hydrochloric acid in 1,4-dioxane (4 M, 11 mL, 45.26 mmol), and stir at room temperature for 2 h. After the reaction is complete, concentrate under reduced pressure to obtain N-methyl-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride (yellow solid, 1.3 g, 2-step yield: 88.8%).

[0806] Intermediate C7. Preparation of N-cyclopropyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0807]

[0808] Step 1: Dissolve (2R,3S)-3-(cyclopropylamino)-2-methylazetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) in methanol (10 mL), add sodium cyanoborohydride (1.0 g, 16.11 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (2.8 g, 16.11 mmol), heat to 60 ° C and stir for 12 h. After the reaction is complete, cool to room temperature, add water (50 mL) to the reaction solution, extract the mixture with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain (2R,3S)-3-(cyclopropylamino)-2-methylazetidine-1-carboxylic acid tert-butyl ester (white oil, 500 mg, crude product).

[0809] Step 2: Dissolve (2R, 3S)-3-(cyclopropylamino)-2-methylazetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) in dichloromethane (5 mL), add triethylamine (447 mg, 4.4 mmol), cool to 0°C, slowly add methanesulfonic anhydride (920 mg, 5.28 mmol), return to room temperature and stir for 2 hours. After the reaction is complete, cool to 0°C, add water (50 mL) to the reaction solution, extract the mixed solution with dichloromethane (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain (2R, 3S)-3-(N-cyclopropylmethanesulfonamide)-2-methylazetidine-1-carboxylic acid tert-butyl ester (white oil, 350 mg, 52%).

[0810] Step 3: Using (2R,3S)-3-(N-cyclopropylmethanesulfonamide)-2-methylazetidine-1-carboxylic acid tert-butyl ester as raw material, prepare N-cyclopropyl-N-((2R,3S)-2-methylazetidine-3-yl)methanesulfonamide trifluoroacetate (black oil) according to the method of the second step of the synthesis of intermediate C4.

[0811] Intermediate C8. Preparation of N-ethyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0812]

[0813] Step 1: Under nitrogen protection, dissolve tert-butyl (2R,3S)-2-methyl-3-(methylsulfonyl)azetidine-1-carboxylate (595.0 mg, 2.25 mmol) in acetonitrile (10 mL), add cesium carbonate (2.2 g, 6.75 mmol) and iodoethane (421.3 mg, 2.70 mmol) in turn, heat to 100 °C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), 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 (0-50%) as the eluent gradient elution to obtain (2R, 3S)-3-(N-ethylmethylsulfonyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester (white solid, 500 mg, 76.0%). MS (ESI + )m / z=293.3[M+H] + .

[0814] Step 2: Using (2R,3S)-3-(N-ethylmethylsulfonamido)-2-methylazetidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.71 mmol) as raw material, N-ethyl-N-((2R,3S)-2-methylazetidine-3-yl) methanesulfonamide trifluoroacetate (yellow oil, 320 mg, crude product) was prepared according to the method of the second step of the synthesis of intermediate C4. MS (ESI + )m / z=193.2[M+H] + .

[0815] The fourth group of preparation examples: preparation of the final product

[0816] Example 1N-((2S,3R)-1-(1 1 ,5-dimethyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 1), N-methyl-N-((2R,3S)-2-methyl-1-(1 1 -methyl-1 1H-9-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazolocyclononane-4-yl)- 8 -yl)azetidin-3-yl)methanesulfonamide (final product 36), N-((2S,3R)-1-((S)-1 1 ,5-dimethyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide and N-((2S,3R)-1-((R)-1 1 ,5-dimethyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0817]

[0818] Step 1: Dissolve intermediate A1 (1.5 g, 3.5 mmol), intermediate C3 (866.5 mg, 3.2 mmol), Xantphos PdG4 (337.9 mg, 0.35 mmol) and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (15 mL), replace nitrogen, heat to 100 °C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent gradient elution to obtain N-((2R, 3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 750 mg, 40.8%). MS (ESI + )m / z=526.1[M+H] + .

[0819] Step 2: N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (100.0 mg, 0.19 mmol), intermediate B1 (73.3 mg, 0.23 mmol), EPhos Pd G4 (17.5 mg, 0.019 mmol), Ephos (10.16 mg, 0.019 mmol) and cesium carbonate (185.8 mg, 0.57 mmol) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen, heated to 100 ° C and stirred for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography with methanol / dichloromethane (0-10%) as the eluent gradient elution to obtain N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 100 mg, 64.9%). MS (ESI + )m / z=811.6[M+H] + The reaction conditions of this step may also be: Brettphos Pd G4, Cs2CO3 1,4-dioxane, 100°C.

[0820] Step 3: Dissolve N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidine-3-yl)-N-methylmethanesulfonamide (90.0 mg, 0.11 mmol) in tetrahydrofuran (3 mL), replace nitrogen, add TBAF (58.0 mg, 0.22 mmol), raise the temperature to 70 °C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (5 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using methanol / dichloromethane (0-20%) as an eluent gradient elution to obtain N-((2R, 3S)-1-(5-(4-hydroxybutan-2-yl)-3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 50 mg, 79.5%). MS (ESI + )m / z=567.3[M+H] + .

[0821] Step 4: Dissolve N-((2R,3S)-1-(5-(4-hydroxybutan-2-yl)-3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (50.0 mg, 0.088 mmol) in toluene (2 mL), replace nitrogen, add CMBP (42.6 mg, 0.18 mmol), heat to 110 °C and stir for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (5 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high pressure preparative liquid chromatography (column type: Xselect CSH C18 OBD Column, 30*150 mm, 5 μm; mobile phase: acetonitrile / water (0.1% formic acid); flow rate: 60 mL / min; gradient: 12%-42% 10 min; wavelength: 254 / 220 nm) to obtain N-((2S,3R)-1-(1 1 ,5-dimethyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 1) and N-methyl-N-((2R,3S)-2-methyl-1-(1 1 -methyl-1 1 H-9-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazolocyclononane-4-yl)- 8 -yl)azetidin-3-yl)methanesulfonamide (final product 36).

[0822] Final product 1: light yellow solid, MS (ESI + )m / z=549.3[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.18(d,J=11.7Hz,1H),9.17-9.05(m,2H),8.28(dd,J=4.8,0.9Hz,1H) ,7.94(d,J=2.5Hz,1H),7.53(d,J=8.1Hz,1H),6.90-6.81(m,1H),6.76-6.58(m,1H),4.66(t,J=7 .4Hz,1H),4.46-4.33(m,2H),4.22(q,J=6.7Hz,1H),3.87-3.72(m,5H),2.96(d,J=2.1Hz,3H),2. 82(d,J=3.3Hz,3H),2.28-2.10(m,1H),2.02-1.79(m,2H),1.58-1.47(m,3H),1.47-1.39(m,3H).

[0823] Final product 36: off-white solid, MS (ESI + )m / z=549.3[M+H] + . 1H NMR (300MHz, DMSO-d6) δ10.21(s,1H),9.10(s,1H),9.00(s,1H),8.31(d,J=5.8Hz,1H),7.89(s,1H ),7.38(d,J=7.7Hz,1H),6.91(d,J=5.8Hz,1H),6.61(d,J=7.8Hz,1H),4.64(t,J=7.4Hz,1H),4.43( t,J=6.2Hz,1H),4.37-4.28(m,1H),4.27-4.14(m,2H),3.84(t,J=7.2Hz,1H),3.75(s,3H),3.29-3 .21(m,1H),3.19-3.08(m,1H),2.95(s,3H),2.82(s,3H),2.00-1.71(m,4H),1.41(d,J=5.9Hz,3H).

[0824] The final product 1 was separated by chiral preparative column (column type: CHIRALPAK IG 2*25cm, 5μm; mobile phase A: cyclohexane / dichloromethane (0.5% 2M NH3-MeOH) = 3 / 1, mobile phase B: EtOH; flow rate: 20mL / min; wavelength: 220 / 254nm) to obtain the final product 2. The specific configuration of the final product 2 is unknown.

[0825] Final product 2:

[0826] Pale yellow solid, MS (ESI + )m / z=549.3[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ10.19(s,1H),9.09(d,J=14.7Hz,2H),8.28(d,J=5.8Hz,1H) ,7.92(s,1H),7.52(d,J=8.0Hz,1H),6.83(d,J=5.9Hz,1H),6.68(d,J=8.1Hz,1H),4. 64(t,J=7.4Hz,1H),4.53-4.37(m,3H),4.26-4.14(m,1H),3.84-3.78(m,5H),2.94( s,3H),2.80(s,3H),2.22-1.88(m,2H),1.49(d,J=6.8Hz,3H),1.41(d,J=5.9Hz,3H).

[0827] Preparation of the final products 10, 12, 13, 78-79, 84, 110-111, 117, 119, 124, 139, 145, 148, 154-155, 166-167, 176, 187, 190 of Examples 2-21

[0828] Using intermediates A1-A9, intermediates B1-B10, and intermediates C1-C8 as raw materials, final products 10, 12, 13, 78-79, 84, 110-111, 117, 119, 124, 139, 145, 148, 154-155, 166-167, 176, 187, and 190 were prepared according to the synthesis method of Example 1. As shown in Table 1. The first step coupling conditions can also be: Pd2(dba)3, BINAP, tBuONa, toluene, 90-100°C or Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 100°C. The third step deprotection reaction conditions can also be: TBAF, TMEDA, THF, 70°C.

[0829] Table 1 Characterization data of final products 10, 12, 13, 78-79, 84, 110-111, 117, 119, 124, 139, 145, 148, 154-155, 166-167, 176, 187, 190

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837] Example 22 Preparation of Final Product 23 and Final Product 42

[0838]

[0839] Step 1: Using N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide and intermediate B2 as raw materials, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(4-(4-methoxybenzyl)oxy-2-methylpyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide was prepared according to the method of Step 2 of Example 1. MS (ESI + )m / z=812.4[M+H] + .

[0840] Step 2: At room temperature, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(4-(4-methoxybenzyl)oxy-2-methylpyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (550.0 mg, 0.68 mmol), dichloromethane (9 mL) and trifluoroacetic acid (3 mL) were added to a 25 mL single-mouth bottle in sequence. The mixed solution was stirred at room temperature for 1 h. After the reaction was complete, it was concentrated under reduced pressure. At room temperature, ethanol (4 mL), tetrahydrofuran (12 mL), water (4 mL), and lithium hydroxide (357.1 mg, 14.91 mmol) were added to the above residue in sequence, and the mixed solution was stirred at room temperature for 2 h. After the reaction is complete, water (10 mL) is added to dilute, and the mixture is extracted with ethyl acetate (150 mL × 3) and dichloromethane (150 mL × 4). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain N-((2R, 3S)-1-(3-((2-(4-hydroxy-2-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 450.0 mg, crude product). MS (ESI + )m / z=578.3[M+H] + .

[0841] Step 3: Using N-((2R,3S)-1-(3-((2-(4-hydroxy-2-methylpyridin-3-yl)pyrimidin-4-yl)amino)-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as raw material, prepare N-((2R,3S)-1-(1 2,5-dimethyl-8-oxo-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridylcyclooctyl-4 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 23, crude product). The crude final product 23 was separated and purified by chiral preparation column (column type: CHIRALPAK IG 2*25cm, 5μm; mobile phase: cyclohexane (0.5% 2M NH3-MeOH) and EtOH:DCM=1:1; flow rate: 20mL / min; wavelength: 220 / 254nm) to obtain the final product 42, the specific configuration of the final product 42 is unknown.

[0842] Final product 42:

[0843] MS (ESI + )m / z=560.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.48(s,1H),9.08(s,1H),8.53(d,J=5.8Hz,1H),8.38(d,J=5.9Hz,1H), 7.55-7.28(m,2H),7.06(d,J=5.9Hz,1H),6.61(d,J=8.0Hz,1H),4.87(t,J=11.2Hz,1H),4.67(t,J=7.4Hz,1H), 4.49-4.39(m,1H),4.29-4.16(m,1H),4.10-3.92(m,1H),3.83(t,J=7.2Hz,1H),3.30-3.20(m,1H),2.95(s,3H) ,2.82(s,3H),2.50-2.48(m,1H),2.38(s,3H),2.14-2.00(m,1H),1.48(d,J=6.6Hz,3H),1.40(d,J=6.0Hz,3H).

[0844] Example 23 1 2 ,2 6 -Dimethyl-4 8 Preparation of -((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane (final product 84)

[0845]

[0846] Using 5-(3-(tert-butyldimethylsilyl)oxy)propyl)-3-chloro-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (prepared using intermediate A9 and intermediate C1 as raw materials according to the first step of synthesizing the final product) and intermediate B11 as raw materials, the final product 91 was prepared according to the above-mentioned method for synthesizing the final product 23.

[0847] MS (ESI + )m / z=545.2[M+H] + . 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),9.06(s,1H),8.50(d,J=6.3Hz,1H),7.59(s,1H),7 .31(d,J=7.7Hz,1H),7.09(d,J=6.5Hz,1H),6.60(s,1H),6.41(d,J=7.7Hz,1H),4.71(t,J=7.5 Hz,1H),4.38-4.32(m,2H),4.31-4.21(m,1H),3.72(t,J=6.9Hz,1H),3.46-3.26(m,2H),3.14- 2.99(m,3H),2.97(s,3H),2.72(s,3H),2.53(s,3H),2.19-2.04(m,2H),1.52(d,J=6.0Hz,3H).

[0848] Example 24 5-Methyl-4 8 Preparation of -((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8-oxo-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridylcyclooctane (final product 71)

[0849]

[0850] Step 1 and Step 2: Using Intermediate A1, Intermediate C1 and Intermediate B3 as raw materials, 5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-N-(2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine was prepared according to the methods of Step 1 and Step 2 of Example 1. MS (ESI + )m / z=677.4[M+H] + .

[0851] Step 3: Under nitrogen protection, 5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-N-(2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (190 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL) in a 40 mL single-necked bottle, and TBAF (1.1 mL, 1.1 mmol) was added under stirring. 2mmol), heated to 70℃ and stirred for 1h, cooled to room temperature, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as eluent to obtain 3-(3-((2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-5-yl)butan-1-ol (yellow solid, 150mg, 85.5%). MS (ESI + )m / z=563.4[M+H] + .

[0852] Step 4: Under nitrogen protection, 3-(3-((2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)amino)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-5-yl)butan-1-ol (145 mg, 0.26 mmol) and lithium tri-sec-butylborohydride tetrahydrofuran solution (1 M, 5 mL) were added to a 40 mL single-necked bottle in sequence and stirred at room temperature for 20 min. Methanol (5 mL) was added to quench the reaction, and the reaction was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high pressure preparative liquid chromatography using acetonitrile / water (0.1% ammonia water) as an eluent to obtain a white solid 3-(4-((5-(4-hydroxybutan-2-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)pyridin-4-ol (50 mg, 31.8%). MS (ESI + )m / z=549.3[M+H] + The reaction conditions of this step can also be: NaH (60%), ethanethiol, DMF, 120°C.

[0853] Step 5: Using 3-(4-((5-(4-hydroxybutan-2-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)pyridin-4-ol as a raw material, prepare 5-methyl-4-(((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)pyridin-4-ol according to the method of Step 4 of Example 1. 8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-8-oxo-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridylcyclooctane (final product 71).

[0854] MS (ESI + )m / z=531.2[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ10.35(d,J=3.8Hz,1H),9.45(d,J=6.5Hz,1H),9.24(d,J=11.4Hz,1H), 9.07(s,1H),8.50(t,J=5.7Hz,2H),7.49-7.38(m,2H),7.06(d,J=5.8Hz,1H),6.54(t,J=7.0Hz, 1H),4.77-4.65(m,2H),4.24-4.13(m,1H),4.10-4.01(m,1H),3.70-3.59(m,1H),3.58-3.50(m ,3H),2.99(s,3H),2.93-2.84(m,1H),2.28-2.13(m,1H),1.66-1.51(m,1H),1.50-1.37(m,6H).

[0855] Preparation of final products 58 and 60 of Examples 25-26

[0856] The above-mentioned preparation method of the final product 71 was adopted, and the intermediate A1 or A9, the intermediate B7, and the intermediate C3 were used as raw materials to prepare the final products 58 and 60. As shown in Table 2.

[0857] Table 2 Characterization data of final products 58 and 60

[0858]

[0859]

[0860] Example 27 N-methyl-N-((2R,3S)-2-methyl-1-(5-methyl-8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 -yl)azetidin-3-yl)methanesulfonamide (final product 20), preparation of final product 22

[0861]

[0862] Step 1: Under nitrogen protection, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (595 mg, 1.13 mmol) was dissolved in 1,4-dioxane (10 mL) in a 40 mL reaction bottle, and 2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine (Intermediate B4, 378 mg, 1.36 mmol), Josiphos (49 mg, 0.11 mmol), Josiphos Pd G3 (105 mg, 0.11 mmol) and cesium carbonate (1.11 g, 3.4 mmol) were heated to 100 ° C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (30 mL), 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 methanol / dichloromethane (0-50%) as the eluent gradient elution to obtain N-((2R,3S)-1-(3-((2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)amino)-5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 560 mg, 64.4%). MS (ESI + )m / z=768.4[M+H] + .

[0863] Step 2: In a 100 mL reaction bottle, N-((2R,3S)-1-(3-((2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)amino)-5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (595 mg, 0.73 mmol) was dissolved in ethanol (15 mL), and ammonium formate (0.46 g, 73.01 mmol) and palladium carbon (116 mg, 1. 11mmol), heated to 60℃ and stirred for 2h. After the reaction was complete, cooled to room temperature, the reaction solution was filtered with diatomaceous earth, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow oil, 320mg, crude product). MS (ESI + )m / z=678.4[M+H] + .

[0864] Step 3: Under nitrogen protection, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (320 mg, 0.47 mmol) was dissolved in tetrahydrofuran (10 mL) in a 40 mL reaction bottle, and triethylamine trihydrofluoride (0.11 g, 0.71 mmol) was added under ice bath. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was cooled to 0°C, and water (5 mL) was added to quench the reaction. The mixed solution was extracted with dichloromethane (30 mL×3), the organic phases were combined, 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 using ethyl acetate / petroleum ether (0-60%) as eluent to obtain N-((2R,3S)-1-(5-(4-hydroxybutan-2-yl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow oil, 157 mg, 59.0%). MS (ESI + )m / z=564.4[M+H] + .

[0865] Step 4: Under nitrogen protection, in a 40 mL reaction bottle, N-((2R,3S)-1-(5-(4-hydroxybutan-2-yl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (150 mg, 0.28 mmol) was dissolved in toluene (5 mL), and then cyanomethylenetributylphosphine (0.67 g, 2.79 mmol) was added, the temperature was raised to 100 ° C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, and water (5 mL) was added to quench the reaction. The mixed solution was extracted with dichloromethane (10 mL×3), the organic phases were combined, 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 using methanol / dichloromethane (0-10%) as eluent to obtain N-methyl-N-((2R,3S)-2-methyl-1-(5-methyl-8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8-yl)azetidin-3-yl)methanesulfonamide (crude product). The crude product was subjected to chiral separation (column: CHIRALPAK IE, 2*25cm, 5μm; mobile phase A: methyl tert-butylamine (0.5% 2M ammonia methanol); mobile phase B: methanol / dichloromethane (1 / 1), flow rate: 20mL / min; wavelength: 254nm, RT1 (min): 17.375; RT2 (min): 20.88) to obtain N-methyl-N-((2R,3S)-2-methyl-1-((S)-5-methyl-8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 -yl)azetidin-3-yl)methanesulfonamide and N-methyl-N-((2R,3S)-2-methyl-1-((R)-5-methyl-8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 -yl)azetidin-3-yl)methanesulfonamide (final product 22), the specific R or S configuration of the final product 22 is unknown.

[0866] Final product 22:

[0867] Off-white solid.MS(ESI + )m / z=546.4[M+H] + . 1 H NMR (300MHz, Methanol-d4) δ9.48(s,1H),9.09(s,1H),9.03(s,1H),8.40(d,J=6.0Hz,1H),8.34(d,J=5.9Hz ,1H),7.42(d,J=7.9Hz,1H),7.31(d,J=6.1Hz,1H),6.84(d,J=5.9Hz,1H),6.62(d,J=8.0Hz,1H),4.70-4.64( m,1H),4.52(t,J=7.4Hz,1H),4.42-4.31(m,1H),4.16(q,J=6.7Hz,1H),4.03(d,J=9.3Hz,1H),3.73(t,J=7.1 Hz,1H),3.57-3.42(m,1H),2.87-2.79(m,6H),2.31(t,J=13.4Hz,1H),1.66-1.51(m,1H),1.48-1.36(m,6H).

[0868] Example 28 Preparation of Final Product 38

[0869] Using intermediate A2, intermediate B4 and intermediate C3 as raw materials, final product 38 was prepared according to the synthesis method of final product 22. The specific configuration of final product 38 is unknown.

[0870] Final product 38:

[0871] White solid.MS (ESI + )m / z=532.1[M+H] + . 1 H NMR(300MHz,Chloroform-d)δ9.46(s,1H),9.19(s,1H),9.07(s,1H),8.65-8.54(m, 2H),8.31(s,1H),7.55(d,J=8.0Hz,1H),7.18(d,J=6.6Hz,1H),6.77(d,J=5.8Hz,1H) ,6.63(d,J=8.1Hz,1H),4.65(t,J=7.6Hz,1H),4.52-4.33(m,3H),4.33-4.22(m,1H) ,4.05-3.87(m,2H),2.97-2.83(m,6H),1.62(d,J=7.4Hz,3H),1.51(d,J=6.1Hz,3H).

[0872] Example 29 Preparation of Final Product 73

[0873] Using intermediate A1, intermediate B4 and intermediate C1 as raw materials, final product 71 was prepared according to the synthesis method of final product 22, and final product 71 was purified by high pressure preparative liquid chromatography (column type: XBridge Prep Shield RP18 OBD Column, 30*150mm, 5μm; mobile phase: acetonitrile / water (0.1% formic acid); flow rate: 60mL / min; gradient: 5%-35% 7min; wavelength: 254nm) to obtain final product 73. The specific configuration of final product 73 is unknown.

[0874] Final product 73:

[0875] Yellow solid.MS (ESI + )m / z=531.4[M+H] + . 1H NMR(300MHz,Methanol-d4)δ9.40(s,1H),9.06(s,1H),8.98(s,1H),8.38(d,J=6.0Hz,1H), 8.32(d,J=6.0Hz,1H),7.34(d,J=7.9Hz,1H),7.28(d,J=6.2Hz,1H),6.81(d,J=5.9Hz,1H),6 .51(d,J=7.9Hz,1H),4.69-4.47(m,3H),4.25-4.12(m,1H),3.98(d,J=9.5Hz,1H),3.57-3. 34(m,3H),2.96-2.84(m,4H),2.25(t,J=13.2Hz,1H),1.61-1.47(m,1H),1.46-1.33(m,6H).

[0876] Example 30 N-((2R,3S)-1-(9-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclononane-4 8 Preparation of -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 129)

[0877]

[0878] Using N-((2R,3S)-1-(3-chloro-5-(4-hydroxybutyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (prepared using intermediate A8 and intermediate C3 as raw materials according to the first step method of Example 1) and intermediate B4 as raw materials, the final product 129 was prepared according to the first step, second step and fourth step methods of synthesizing the final product 20.

[0879] MS (ESI + )m / z=546.3[M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),9.08(s,1H),8.95(s,1H),8.67(s,1H),8.42(d,J=5.6Hz,1H),7.77- 7.63(m,1H),7.43(d,J=7.8Hz,1H),6.92(d,J=5.6Hz,1H),6.63(d,J=7.6Hz,1H),6.26(d,J=7.6Hz,1H),4. 65(t,J=7.4Hz,1H),4.48-4.41(m,1H),4.25-4.17(m,3H),3.83(t,J=7.2Hz,1H),3.33-3.22(m,1H),3.03- 2.89(m,4H),2.83(s,3H),1.99-1.91(m,2H),1.82-1.71(m,1H),1.69-1.58(m,1H),1.41(d,J=6.0Hz,3H).

[0880] Example 31 N-methyl-N-((2R,3S)-2-methyl-1-(5-methyl-8-oxa-3,5-diaza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 Preparation of 2-(2-yl)azetidin-3-yl)methanesulfonamide (final product 25)

[0881]

[0882] Step 1: Under nitrogen protection, in a 40 mL reaction bottle, N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine (Intermediate A3, 700 mg, 1.47 mmol) was dissolved in toluene (7 mL), and N-methyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide (Intermediate C3, 393 mg, 2.21 mmol), Pd2(dba)3 (134.6 mg, 0.15 mmol), BINAP (91.5 mg, 0.15 mmol) and sodium tert-butoxide (424.0 mg, 4.41 mmol) were added in sequence, and the temperature was raised to 90 ° C and stirred for 1 h. After the reaction was complete, the temperature was lowered to room temperature, saturated brine (30 mL) was added, the mixed solution was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), 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 using ethyl acetate / petroleum ether (5-20%) as eluent to obtain N-((2R,3S)-1-(5-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow oil, 500 mg, 64.7%). MS (ESI + )m / z=527.3[M+H] + .

[0883] Step 2: Under nitrogen protection, N-((2R,3S)-1-(5-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (500 mg, 0.95 mmol) was dissolved in tetrahydrofuran (20 mL) in a 250 mL reaction bottle, TBAF (2.35 mL, 1 M THF solution, 1.423 mmol) was added with stirring, the temperature was raised to 60 ° C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, water (50 mL) was added to quench the reaction, and the mixed solution was extracted with dichloromethane (50 mL×3), the organic phases were combined, 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 (0-60%) as eluent to give N-((2R,3S)-1-(3-chloro-5-((2-hydroxyethyl)(methyl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 300 mg, 76.6%).

[0884] Step 3: Under nitrogen protection, 2-(4-fluoropyridin-3-yl)pyrimidin-4-amine (270 mg, 1.420 mmol) was dissolved in 1,4-dioxane (10 mL) in a 100 mL reaction bottle, and N-((2R,3S)-1-(3-chloro-5-((2-hydroxyethyl)(methyl)amino)isoquinolin-8-yl)-2-methylazetidine-3-yl)-N-methylmethanesulfonamide (290 mg, 0.70 mmol) and potassium hydroxide (239 mg, 4.3 mmol) were added in sequence. The temperature was raised to 100 ° C and stirred for 4 h. After the reaction was complete, the temperature was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine (20 mL), 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 using methanol / dichloromethane (0-15%) as eluent to give N-((2R,3S)-1-(5-((2-((3-(4-aminopyrimidin-2-yl)pyridin-4-yl)oxy)ethyl)(methyl)amino)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 130 mg, 31%). MS (ESI + )m / z=583.3[M+H] + .

[0885] Step 4: Under nitrogen protection, N-((2R,3S)-1-(5-((2-((3-(4-aminopyrimidin-2-yl)pyridin-4-yl)oxy)ethyl)(methyl)amino)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (110 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) in a 40 mL reaction bottle, and Ephos (10 mg, 0.019 mmol), Ephos Pd G4 (35 mg, 0.038 mmol) and cesium carbonate (184 mg, 0.57 mmol) were added in sequence, and the temperature was raised to 100 ° C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, and water (5 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-10%) as eluent to obtain a crude product, which was then purified by high pressure preparative liquid chromatography (column type: XBridgePrep C18 OBD Column, 19*250 mm, 5 μm; mobile phase: acetonitrile / water (0.1% ammonium bicarbonate); flow rate: 25 mL / min; gradient: 28%-50% 10 min; wavelength: 254 nm, RT1 (min): 8.99) to obtain N-methyl-N-((2R,3S)-2-methyl-1-(5-methyl-8-oxa-3,5-diaza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 -yl)azetidin-3-yl)methanesulfonamide (10.2 mg, 9.8%).

[0886] Yellow solid, MS (ESI + )m / z=547.2[M+H] + . 1 H NMR(300MHz,Methanol-d4)δ9.74(s,1H),9.28(s,1H),9.12(s,1H),8.51(d,J=6.0Hz,1 H),8.45(d,J=5.9Hz,1H),7.45(d,J=6.1Hz,1H),7.33(d,J=8.2Hz,1H),6.94(d,J=5.9H z,1H),6.70(d,J=8.2Hz,1H),4.86-4.83(m,3H),4.66-4.52(m,2H),4.50-4.38(m,1H), 4.25(q,J=6.8Hz,1H),3.76(t,J=7.1Hz,1H),3.00-2.78(m,9H),1.48(d,J=6.1Hz,3H).

[0887] Example 32 N-methyl-N-((2R,3S)-2-methyl-1-(1 1 -methyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 Preparation of -yl)azetidin-3-yl)methanesulfonamide (final product 34)

[0888]

[0889] The first step and the second step: using intermediate A5, intermediate C3 and intermediate B1 as raw materials, respectively, according to the method of the first step and the second step of Example 1, N-methyl-N-((2R,3S)-2-methyl-1-(3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)azetidin-3-yl)methanesulfonamide was prepared, MS (ESI + )m / z=767.4[M+H] + .

[0890] Step 3: In a 40 mL reaction bottle, dissolve N-methyl-N-((2R,3S)-2-methyl-1-(3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)azetidin-3-yl)methanesulfonamide (200 mg, 0.26 mmol) in methanol (10 mL), then add p-toluenesulfonic acid (0.22 g, 1.30 mmol), heat to 60 ° C and stir for 16 h. After the reaction was complete, the temperature was lowered to room temperature, and the reaction solution was separated and purified by preparative liquid chromatography using acetonitrile / water (0-30%) as the eluent to obtain N-((2R,3S)-1-(3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(3-hydroxypropyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (yellow solid, 90 mg, 62.5%). MS (ESI + )m / z=553.3[M+H] + .

[0891] Step 4: Using N-((2R,3S)-1-(3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(3-hydroxypropyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as a raw material, N-methyl-N-((2R,3S)-2-methyl-1-(1 1 -methyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 -yl)azetidin-3-yl)methanesulfonamide.

[0892] Yellow solid.MS (ESI + )m / z=535.4[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),9.08(s,1H),9.03(s,1H),8.30(d,J=5.7Hz,1H),7.95(s,1H), 7.46(d,J=7.8Hz,1H),6.85(d,J=5.8Hz,1H),6.65(d,J=7.9Hz,1H),4.70-4.62(m,1H),4.50-4.37(m ,2H),4.37-4.28(m,1H),4.26-4.16(m,1H),3.87-3.79(m,1H),3.78(s,3H),3.22-3.15(m,1H),3.15 -3.06(m,1H),2.96(s,3H),2.82(s,3H),2.31-2.19(m,1H),2.18-2.10(m,1H),1.41(d,J=6.0Hz,3H).

[0893] Example 33 N-((2R,3S)-1-(8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4 8 Preparation of -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 39)

[0894]

[0895] Step 1: Under nitrogen protection, N-((2R,3S)-1-(3-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (300 mg, 0.62 mmol) was dissolved in 1,4-dioxane (8 mL) in a 40 mL reaction bottle, and intermediate B4 (0.17 g, 0.62 mmol), Ephos Pd G4 (0.06 g, 0.06 mmol), Ephos (0.03 g, 0.06 mmol) and cesium carbonate (0.61 g, 1.87 mmol) were heated to 100 °C and stirred for 12 h. After the reaction was complete, the temperature was cooled to room temperature, and water (30 mL) was added to quench the reaction. The mixed solution was extracted with dichloromethane (30 mL×3), and the combined organic phases were washed with saturated brine (15 mL), 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 using methanol / dichloromethane (0-15%) as eluent to give N-((2R,3S)-1-(3-((2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (white solid, 200 mg, 44.4%). MS (ESI + )m / z=724.3[M+H] + .

[0896] Step 2: Using N-((2R,3S)-1-(3-((2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as raw material, N-((2R,3S)-1-(3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide was prepared according to the method of the second step of synthesizing the final product 20. MS (ESI + )m / z=634.3[M+H] + .

[0897] Step 3: Using N-((2R,3S)-1-(3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as raw material, N-((2R,3S)-1-(5-(3-hydroxypropyl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide was prepared according to the method of step 3 of synthesizing the final product 34. MS (ESI + )m / z=550.1[M+H] + .

[0898] Step 4: Using N-((2R,3S)-1-(5-(3-hydroxypropyl)-3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as a raw material, N-((2R,3S)-1-(8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(3,4)-pyridinecyclooctane-4-yl) was prepared according to the method of Step 4 of Example 1. 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 39).

[0899] MS (ESI + )m / z=532.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.68(s,1H),9.60(s,1H),9.17-9.05(m,2H),8.43(d,J=6.1Hz,1H), 7.84-7.74(m,1H),7.50(d,J=7.8Hz,1H),6.95(d,J=6.1Hz,1H),6.65(d,J=7.8Hz,1H),6.39( d,J=7.5Hz,1H),4.70(t,J=7.5Hz,1H),4.55-4.41(m,1H),4.28-4.11(m,3H),3.87(t,J=7.2H z,1H),2.97(s,3H),2.94-2.87(m,2H),2.83(s,3H),2.27-2.08(m,2H),1.42(d,J=6.0Hz,3H).

[0900] Example 34 N-((2R,3S)-1-(1 1 ,5-dimethyl-1 1H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 Preparation of -yl)-2-methylazetidin-3-yl)methanesulfonamide (final product 137)

[0901]

[0902] Step 1: Using 8-bromo-3-chloroisoquinoline (1.5 g, 6.19 mmol) and intermediate C2 (1.9 g, 6.80 mmol) as raw materials, N-((2R,3S)-1-(3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 800 mg, 39.7%) was prepared according to the method of synthesizing the final product 1, step 1. MS (ESI + )m / z=326.1[M+H] + .

[0903] Step 2: Dissolve N-((2R,3S)-1-(3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (800.0 mg, 2.46 mmol) in acetic acid (8 mL), slowly add NIS (552.4 mg, 2.46 mmol), and stir at room temperature for 5 min. After the reaction is complete, add sodium thiosulfate solution (200 mL) to the reaction solution, extract the mixture with ethyl acetate (100 mL×2), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 3) as eluent to obtain N-((2R,3S)-1-(3-chloro-5-iodoisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 900 mg, 81.1%). MS (ESI + )m / z=451.9[M+H] + .

[0904] Step 3: Under nitrogen protection, N-((2R,3S)-1-(3-chloro-5-iodoisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (900.0 mg, 1.99 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1 v / v, 11 mL), and Pd(dppf)Cl2 (145.8 mg, 0.20 mmol), K2CO3 (550.7 mg, 3.98 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (394.6 mg, 1.99 mmol) were added in sequence, and the temperature was raised to 100°C and stirred for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as eluent to obtain N-((2R, 3S)-1-(3-chloro-5-(4-hydroxy-1-ene-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 300 mg, 38.0%). MS (ESI + )m / z=396.1[M+H] + .

[0905] Step 4: Under nitrogen protection, N-((2R,3S)-1-(3-chloro-5-(4-hydroxy-1-ene-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (300.0 mg, 0.76 mmol) was dissolved in ethyl acetate (5 mL), and platinum dioxide (68.8 mg, 0.30 mmol) was added to replace hydrogen and stirred at room temperature for 2 h. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain N-((2R,3S)-1-(3-chloro-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 300 mg, 99.5%). MS (ESI + )m / z=398.1[M+H] + .

[0906] Step 5: Dissolve N-((2R,3S)-1-(3-chloro-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (300.0 mg, 0.75 mmol) in DCM (6 mL), add imidazole (154.0 mg, 2.26 mmol), cool to 0°C, add TBSCl (170.4 mg, 1.13 mmol), and stir at room temperature for 16 h. After the reaction was complete, water (20 mL) was added to the reaction solution, the mixed solution was extracted with dichloromethane (20 mL×3), the combined organic phases were washed with saturated brine (20 mL), 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 / 10) as eluent to obtain N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butane-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 300 mg, 77.7%). MS (ESI + )m / z=512.2[M+H] + .

[0907] Step 6: Under nitrogen protection, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butane-2-yl)-3-chloroisoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (300.0 mg, 0.59 mmol) was dissolved in 1,4-dioxane (5 mL), and Brettphos Pd G4 (107.8 mg, 0.12 mmol), Cs2CO3 (381.7 mg, 1.17 mmol) and 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (Intermediate B1, 188.3 mg, 0.59 mmol) were added in sequence, and the temperature was raised to 100 °C and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as the eluent to obtain N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 200 mg, 42.8%). MS (ESI + )m / z=797.3[M+H] + .

[0908] Step 7: Dissolve N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (200.0 mg, 0.25 mmol) in THF (1 mL), add hydrochloric acid (2 M, 2 mL, 0.50 mmol) dropwise, and stir at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixed solution was back-extracted with ethyl acetate (20 mL×2). The aqueous phase was adjusted to pH 13 with NaOH solution, and then extracted with ethyl acetate (20 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain N-((2R,3S)-1-(5-(4-hydroxybutane-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazamin-3-yl)methanesulfonamide (yellow-green oil, 200 mg, crude product). MS (ESI + )m / z=683.2[M+H] + .

[0909] Step 8: Dissolve N-((2R,3S)-1-(5-(4-hydroxybutan-2-yl)-3-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazepan-3-yl)methanesulfonamide (200.0 mg, 0.29 mmol) in DCM (1 mL), add TFA (1 mL) dropwise, and stir at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was adjusted to pH 13 by adding NaOH (1M) solution, stirred for 1 h, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as eluent to obtain N-((2R,3S)-1-(3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 100 mg, two-step yield: 72.1%). MS (ESI + )m / z=553.2[M+H] + .

[0910] Step 9: Dissolve N-((2R,3S)-1-(3-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-5-(4-hydroxybutan-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (80.0 mg, 0.14 mmol) in THF (1 mL), cool to 0°C, add PPh3 (113.9 mg, 0.43 mmol) and DBAD (129.5 mg, 0.43 mmol) in turn, and stir at room temperature for 1 h. After the reaction was completed, H2SO4 solution (1M, 10mL) was added to the reaction solution, and the mixed solution was back-extracted with ethyl acetate (10mL×2). The aqueous phase was adjusted to pH 13 with NaOH solution (1M), and then extracted with ethyl acetate (10mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high pressure preparative liquid chromatography to obtain N-((2R,3S)-1-(1 1 ,5-dimethyl-1 1 H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazole cyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 5 mg, 6.3%).

[0911] MS (ESI + )m / z=534.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.18-9.04(m,2H),8.28-8.19(m,1H),8.08(s,1H),7.58(dd,J=8.0,2. 8Hz,1H),6.97(d,J=5.4Hz,1H),6.80-6.62(m,1H),4.74(t,J=7.0Hz,1H),4.60-4.48(m,1H),4. 39-4.29(m,1H),4.19-4.12(m,1H),4.12-3.81(m,3H),3.74(s,2H),3.60-3.52(m,1H),2.94(d ,J=3.8Hz,3H),2.20-2.03(m,1H),1.94-1.83(m,1H),1.59-1.46(m,3H),1.40(t,J=5.8Hz,3H).

[0912] Preparation of final products 61, 77, 83, 86, 98, 123, 140, 157, 189, 193 of Examples 35-42

[0913] The preparation method of the final product 137 was adopted, and the intermediates B1-B10 and intermediates C1-C5 were used as raw materials to prepare the final products 61, 77, 83, 86, 98, 123, 140, 157, 189, and 193. As shown in Table 3. The first step coupling reaction conditions can also be: Xantphos Pd G3, Cs2CO3, dioxane, 100°C. The second step iodination reaction conditions can also be: NIS, acetonitrile, acetic acid, rt. The fifth step TBS protecting group addition reaction conditions can also be: imidazole, TBSCl, DMAP, DCM. The sixth step coupling reaction conditions can also be: EPhos Pd G4, Ephos, Cs2CO3, 1,4-dioxane, 100°C. The deprotection reaction in the seventh and eighth steps can be completed in one step using TBAF, THF, 70°C; if intermediate B3, B7 or B8 is used as a raw material, the demethylation reaction conditions in the eighth step are: DMF, NaH, ethanethiol, DMF, 120°C. The Mitsunobu reaction conditions in the ninth step can also be: CMBP, toluene, 100-110°C.

[0914] Table 3 Characterization data of final products 61, 77, 83, 86, 98, 123, 140, 157, 189, 193

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] Preparation of comparative compound A

[0921]

[0922] According to the synthesis method of Example 1, intermediate A1, intermediate C1 and intermediate B1 were used as raw materials to prepare comparative compound A according to the method of Example 1. MS (ESI + )m / z=534.2[M+H] + . 1H NMR (300MHz, DMSO-d6) δ10.13(s,1H),9.08(d,J=8.7Hz,2H),8.29(d,J=5.8Hz,1H),7.93(s,1H),7.50( d,J=8.0Hz,1H),6.83(d,J=5.8Hz,1H),6.60(d,J=8.1Hz,1H),4.67(t,J=7.5Hz,1H),4.49-4.41(m,1H) ,4.38-4.30(m,1H),4.25-4.15(m,1H),3.82(s,3H),3.70-3.59(m,1H),3.60-3.50(m,3H),2.99(s,3H) ,2.93-2.84(m,1H),2.35-2.24(m,1H),1.89-1.83(m,1H),1.49(d,J=7.2Hz,3H),1.42(d,J=6.9Hz,3H).

[0923] Experimental example

[0924] 1. Cell proliferation inhibition experiment

[0925] CellTiter-Glo TM The live cell detection kit uses luciferase as the detection substance. Luciferase requires the participation of ATP in the luminescence process. Add CellTiter-Glo to the cell culture medium. TM Reagents, measuring luminescence values, light signals are proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by using the CellTiter-Glo kit to detect ATP content, cell proliferation can be detected.

[0926] In this experiment, the celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the above-prepared compounds in tumor cell lines Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975, PC9, Ba / F3 EGFR wt and A431, and the 50% inhibitory concentration (IC 50 ).

[0927] 1. Experimental Design

[0928] Compounds were tested on selected cells and vehicle controls were set up for a total of 9 concentrations, with 2 replicates for each concentration.

[0929] 2. Reagents and Consumables

[0930]

[0931]

[0932] 3. Experimental Procedure

[0933] 3.1 Cell culture

[0934] a) All cells were cultured according to the method recommended by ATCC. Cells in the logarithmic growth phase were harvested. Cell viability was tested to ensure that the cell viability was above 90%.

[0935] b) Cell culture medium: add 90 μL of cell suspension to each 96-well plate at the total cell concentration.

[0936] c) Cell culture environment: culture at 37°C, 5% CO2, and 95% humidity.

[0937] 3.2 Drug dilution

[0938] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0939] b) Drug storage: Drug DMSO stock solutions were stored in a room temperature desiccator for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for a longer period of time.

[0940] 3.3 Dosing

[0941] a) When testing the proliferation inhibition activity of Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975 and PC9 cell lines, the drug was diluted 3-fold starting from a concentration of 1 μM, with 10 concentration gradients; when testing the proliferation inhibition activity of Ba / F3 EGFR wt wild-type cell line after adding EGF and the proliferation inhibition activity of A431 cell line, the drug was diluted 3-fold starting from a concentration of 10 μM, with 10 concentration gradients.

[0942] b) Prepare positive control drug and DMSO blank control.

[0943] c) Add 10 μL of 10-fold drug solution to each well of a 96-well plate seeded with cells, and set up 2 replicate wells for each drug concentration.

[0944] d) The cells in the 96-well plate to which the drug had been added were cultured for a further 72 hours at 37° C., 5% CO 2 , and 95% humidity, and then subjected to CTG analysis.

[0945] 3.4 Endpoint plate reading

[0946] a) Melt the CTG reagent, add 50 μL of CTG solution to each well and shake well.

[0947] b) Mix on a shaker for 2 minutes and incubate at room temperature for 10 minutes.

[0948] c) Read the fluorescence value using an enzyme reader.

[0949] 4. Data Processing

[0950] GraphPad Prism 8.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 value.

[0951] Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%.

[0952] 5. Experimental Results

[0953] Table 4 IC values ​​of the compounds for inhibiting proliferation of Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975, PC9, Ba / F3 EGFR wt+EGF and A431 cell lines 50 (nM)

[0954]

[0955]

[0956] Note: LRCS refers to L858R / C797S; LRCS refers to L858R / T790M / C797S; / : not tested;

[0957] The compounds of the present invention inhibit the proliferation activity of Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975, PC9, Ba / F3 EGFR wt+EGF and A431 cell lines. 50 As shown in Table 4.

[0958] As can be seen from Table 4, the compounds of the present invention have good proliferation inhibitory activity against Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975 and PC9 cell lines, and weak inhibitory activity against wild-type EGFR cell lines Ba / F3 EGFR wt+EGF and A431, indicating that the compounds of the present invention have good inhibitory activity and selectivity against cell lines expressing EGFR mutations. The data in Table 4 show that the selectivity of the compounds of the present invention is improved when the L2 groups on the isoquinoline and pyrazole connecting chains have substituents (such as compounds 111, 119, 187, 190) or when the pyrazole 3-position has substituents (such as compound 117).

[0959] 2. Cassette pharmacokinetic test of compounds in mice

[0960] Experimental purpose: Using ICR mice as test subjects, the LC / MS / MS method was used to determine the compound administered by oral gavage (PO), to detect the drug concentration of the compound in plasma at different times, to study the pharmacokinetic behavior of the compound of the present invention in mice, and to evaluate its pharmacokinetic characteristics.

[0961] Drug preparation: The compounds were prepared into clear solutions with 10% NMP + 10% Solutol + 80% Saline as solvents for PO administration. The administration method was cassette dosing. The dosage of the compounds was 10 mg / kg, 15 mg / kg or 20 mg / kg. The pharmacokinetic parameter results are shown in Table 5.

[0962] Table 5 Pharmacokinetic test results of cassette in mice

[0963]

[0964]

[0965] As can be seen from Table 5, the compounds of the present invention have good exposure.

[0966] 3. P-gp substrate evaluation experiment

[0967] 1. Experimental Design

[0968] 1.1 Cell culture

[0969] 1) Use high-glucose DMEM medium containing L-glutamine, supplemented with 10% fetal bovine serum, 0.1 mg / mL streptomycin and 0.6 μg / mL penicillin.

[0970] 2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks. The incubator was set at 37°C, 5% CO2, and relative humidity was maintained at 95%. When the cell confluence reached 70-90%, it could be used for inoculation of Transwell.

[0971] 3) Before cell inoculation, add 50 μL of cell culture medium to each well of the upper chamber of the Transwell, and add 25 mL of cell culture medium to the lower culture plate. Place the culture plate in a 37°C, 5% CO2 incubator for 1 hour before inoculating cells.

[0972] 4) Gently wash the cells with 5 mL of PBS. Discard the PBS, add 1.5 mL of trypsin containing EDTA, and incubate at 37°C for 5 to 10 minutes until the cells are completely detached. Add serum-containing culture medium to terminate the digestion.

[0973] 5) Transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120×g for 10 minutes.

[0974] 6) Resuspend the cells in culture medium to a final concentration of 1.56×10 6 cells / mL.

[0975] 1.2 MDCKII-MDR1 cell inoculation

[0976] 1) Add 50 μL of cell suspension to each well of a 96-well Transwell culture plate, with a final seeding density of 1.45×

[0977] 10 5 cells / cm 2 .

[0978] 2) Start changing the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

[0979] 1.3 Evaluation of cell monolayer integrity

[0980] 1) After 4-8 days of culture, MDCKII-MDR1 and MDCKII should be completely confluent and differentiated. At this point, they can be used for penetration assays.

[0981] 2) The resistance of the monolayer membrane was measured using a resistor meter (Millipore, USA) and the resistance of each pore was recorded.

[0982] 3) After the measurement, place the Transwell culture plate back into the incubator.

[0983] 4) Calculation of resistance value:

[0984] Measure the resistance value (ohms) x film area (cm 2 ) = TEER value (ohm cm2 )

[0985] If TEER value <42ohms·cm 2 , then the hole cannot be used for penetration test.

[0986] 1.4 Drug penetration test

[0987] 1) Take out the MDCKII-MDR1 Transwell culture plate from the incubator. Rinse the cell monolayer twice with HBSS (10 mM HEPES, pH 7.4) buffer and incubate at 37°C for 30 minutes.

[0988] 2) Determine the transport rate of the compound from the apical end to the basolateral end. Add 125 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control drug to each well of the upper chamber (apical end), and add 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the lower chamber (basolateral end).

[0989] 3) Determine the transport rate of the compound from the basolateral end to the apical end. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical end), and add 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer of the test drug or control drug to each well of the lower chamber (basolateral end).

[0990] 4) Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

[0991] 5) After incubation, take 50 μL of samples from each well of the upper and lower chambers of the Transwell culture plate and add them to new sample tubes. Add 4 times the volume of acetonitrile containing internal standards (200nM alprazolam, 200nM labetalol, 200nM diclofenac, 100nM tolbutamide) to the sample tubes, vortex for 5 minutes, and centrifuge at 3,220g for 15 minutes. Pipette 100 μL of the supernatant and dilute with an equal volume of water for LC-MS / MS analysis. All samples were prepared in triplicate.

[0992] 6) The integrity of the cell monolayer membrane after 2 hours of incubation was evaluated by leakage of fluorescent yellow. The fluorescent yellow stock solution was diluted to a final concentration of 100 μM using HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescent yellow solution was added to each well of the upper Transwell insert, and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0993] 2. Data processing

[0994] The data were calculated using Excel. app , unit: cm / s) is calculated using the following formula:

[0995]

[0996] The membrane area in the formula is the Transwell-96 well plate membrane area (0.143 cm 2 ); the incubation time unit is second (s).

[0997] The efflux rate is calculated using the following formula:

[0998]

[0999] Table 3. Efflux rates of the tested compounds

[1000]

[1001]

[1002] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the present invention.

Claims

1. An aminoheteroaryl macrocyclic compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof: in, In Formula I, The A ring is a 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclyl, and the 5-12-membered heteroaryl, 6-12-membered aryl or 3-12-membered heterocyclyl is connected to the NH and M rings respectively through two different atoms; The E ring is a 5-12-membered heteroaryl, a 6-12-membered aryl or a 3-12-membered heterocyclic group, and the 5-12-membered heteroaryl, the 6-12-membered aryl or the 3-12-membered heterocyclic group is connected to NH and X1 respectively through two different atoms; The M ring is a 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl, and the 5-12 membered heteroaryl, 6-12 membered aryl, 3-12 membered heterocyclyl, 3-12 membered cycloalkyl or 3-12 membered cycloalkenyl is connected to the A ring and X2 through 2 different atoms; L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 Heteroalkenylene, the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 2-6 The heteroalkenylene group is optionally substituted by one or more identical or different R 5 replace; X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, S, C(=O) or S(=O)(=W 1 ); R 1 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′; R 2 , R 3 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′; Or two R 2 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl, said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 5-14 membered heteroaryl or 6-14 membered aryl being optionally substituted with one or more R′; R 4 For R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-12 membered cycloalkyl, wherein R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-14 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-12 membered cycloalkyl is optionally substituted with one or more R'; Or, R 4 for R 5 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, C 0-6 Alkyl-6-10 membered aryl, C 0-6 Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′; Or two R 5 together with the atoms to which they are attached form a 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl, said 3-12 membered cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl being optionally substituted with one or more R′; R 1a , R 2a Each independently does not exist or is each independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 、S(=O)(=W 1 )NR e1 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 OR P(=O)OR e2 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′; or R 2 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′; or R 3 and R 1a Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′; R 3a For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR e1 、OC(=O)R e1 、OC(=O)NR e1 R e2 、OS(=O)(=W 1 )R e1 、OS(=O)(=W 1 )NR e1 R e2 , SR e1 、S(=O)(=W 1 )R e1 、S(=O)(=W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 NR e1 S(=O)(=W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 、C(=O)R e1 、C(=O)NR e1 、C(=O)OR e1 , PR e1 R e2 、P(=O)R e1 R e2 、P(=O)2R e1 R e2 、P(=O)OR e2 or oxo (=O), the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are optionally substituted with one or more R′; or R 2a and R 3a Together with the attached C atom, it forms a 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R′; or R 2 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′; or R 3 and R 3a Together with the atoms to which they are attached, they form a 3-12 membered cycloalkyl, a 3-12 membered heterocyclyl, a 6-12 membered aryl or a 5-12 membered heteroaryl, which is optionally substituted with one or more R′; R' is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR f1 、OC(=O)R f1 、OC(=O)NR f1 R f2 、OS(=O)(=W 1 )R f1 、OS(=O)(=W 1 )NR f1 R f2 , SR f1 、S(=O)(=W 1 )R f1 、S(=O)(=W 1 )NR f1 R f2 NR f1 R f2 NR f1 C(=O)R f2 NR f1 S(=O)(=W 1 )R f2 NR f1 C(=O)OR f2 NR f1 C(=O)NR f2 、C(=O)R f1 、C(=O)NR f1 、C(=O)OR f1 、-(O)(OR f1 2. PR f1 R f2 、P(=O)R f1 R f2 、P(=O)2R f1 R f2 、P(=O)OR f2 or oxo (=O); R e1 , R e2 , R f1 , R f2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R″; or R e1 and R e2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; or R f1 and R f2 Together with the atoms to which it is attached, it forms a 3-12 membered heterocyclic group, which is optionally substituted by one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; R″ is a deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 、OC(=O)R g1 、OC(=O)NR g1 R g2 、OS(=O)(=W 1 )R g1 、OS(=O)(=W 1 )NR g1 R g2 , SR g1 、S(=O)(=W 1 )R g1 、S(=O)(=W 1 )NR g1 R g2 NR g1 R g2 NR g1 C(=O)R g2 NR g1 S(=O)(=W 1 )R g2 NR g1 C(=O)OR g2 NR g1 C(=O)NR g2 、C(=O)R g1 、C(=O)NR g1 、C(=O)OR g1 、-(O)(OR g1 2. PR g1 R g2 、P(=O)R g1 R g2 、P(=O)2R g1 R g2 、P(=O)OR g2 or oxo (=O); R g1 and R g2 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl or 3-12 membered cycloalkyl; W 1 None, O or NR g1 ; Y is N or C; represents a single or double bond; R 30 for hydrogen atoms, deuterium atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 3-6 Cycloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more R'; or, two R 30 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′; R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl and C 0-6 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more R'; or, two R 20 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′; Or, R 20 and R 50 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′; Or, R 40 and R 60 Together with the atoms to which they are attached, they form a 3-6-membered cycloalkyl or a 3-7-membered heterocyclyl, wherein the 3-6-membered cycloalkyl or the 3-7-membered heterocyclyl is optionally substituted by one or more R′; m, n, and t are each independently 0, 1, 2, 3, or 4; p is independently 1 or 2.

2. The aminoheteroaryl macrocyclic compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In formula I, ring A is a 5-6 membered heteroaryl group; Preferably, Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole; More preferably, the A ring is selected from the following groups: * a Indicates the connection site with NH, * b Indicates the site of attachment to the M loop; Most preferably, Ring A is selected from the following groups: * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop; Further optionally, in Formula I, the E ring is a 9-10 membered heteroaryl group, and the 9-10 membered heteroaryl group is connected to NH and X1 respectively through 2 different atoms; Preferably, the E ring is More preferably, the E ring is Most preferably, the E ring is selected from Among them, --- or -- means no or a single bond; U 1 Absent or N, CH or C; U 2 Absent or N, CH or C; U 3 N, C, NR 100 , O, S or C(=O); U 4 , U 5 are each independently N or C, and U 4 and U 5 Not all are N; U 6 N or CH; U 7 is C, N, NR 200 , O, S, C(=O), C(=O)O, C(=O)NR 300 , OC(=O) or NR 300 C(=O); R 100 , R 200 or R 300 are independently a hydrogen atom, a deuterium atom, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-6 Alkyl-3-12 membered cycloalkyl or C 0-6 Alkyl-3-12 membered heterocyclic group; When U 1 When it does not exist, U 2 and U 7 Connected by single or double bonds; when U 2 When it does not exist, U 1 and U 3 connected by single or double bonds; When U 1 and U 2 When N or CH, U 1 , U 2 , U 3 , U 4 , U 5 and U 7 At most three of them are N at the same time.

3. The aminoheteroaryl macrocyclic compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In formula I, the M ring is a 5-6 membered heteroaryl or benzene; Preferably, the M ring is pyridine, pyrimidine, pyridazine, imidazole, pyrazole, thiazole, oxazole, triazole, benzene or pyridine N-oxide; More preferably, the M ring is selected from the following groups: * e Indicates the site of connection with the A ring, * f represents the site of connection with X2; Most preferably, the M ring is selected from the following groups: * e Indicates the site of connection with the A ring, * f Indicates the site of connection with X2.

4. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In Formula I, L2 is C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 Heteroalkylene, the C 1-6 Alkylene, C 1-6 Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 1-6 The heteroalkylene group is optionally substituted with one or more identical or different R 5 replace; Preferably, L2 is methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy, wherein the methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene or ethyleneoxy is optionally replaced by one or more identical or different R 5 replace; Among them, R 5 For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl, C 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R′; Or, two R 5 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Preferably, R 5 is a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group or an oxo group; Or, two R 5 together with the atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine being optionally substituted with one or more R′; More preferably, R 5 is a deuterium atom, a halogen, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group or an oxo group; Or, two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl, cyclopropyl; More preferably, L2 is Among them, R 5a , R 5b , R 5c , R 5a ′、R 5b′ , R 5c′ Each independently is R 5 Preferably, R 5a , R 5b , R 5c , R 5a′ , R 5b′ , R 5c′ are independently a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 Alkoxy or oxo, the C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkylamino, di(C 1-6 alkyl)amino, 3-6 membered cycloalkylamino, C 0-2 Alkyl-3-6 membered cycloalkyl, C 0-2 Alkyl-3-7 membered heterocyclic group, C 1-6 The alkoxy group is optionally substituted with one or more hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, 3-6 membered cycloalkyl or oxo substituted; Or, R 5a and R 5a′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Or, R 5b and R 5b′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Or, R 5c and R 5c′ Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Or, R 5a and R 5b Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Or, R 5a and R 5c Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; Or, R 5b and R 5c Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl, a 3-7 membered heterocyclyl or a 3-6 membered cycloalkenyl, which is optionally substituted with one or more R′; More preferably, R 5a , R 5b , R 5c , R 5a′ , R 5b′ , R 5c′ each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo; Or, R 5a and R 5a′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; Or, R 5b and R 5b′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; Or, R 5c and R 5c′ together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; Or, R 5a and R 5b together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; Or, R 5a and R 5c together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; Or, R 5b and R 5c together with the atoms to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine being optionally substituted with one or more R′; wherein R′ is a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a cyclopropyloxy group, or an oxo group.

5. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In Formula I, R 1 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl or oxo, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl are optionally substituted by one or more R'; Preferably, R 1 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group or an oxo group; Preferably, R 2 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic group-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 alkyl-3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 Alkyl and 3-12 membered heterocyclyl-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl; Preferably, R 2 each independently represents a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an isopropoxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group or a diethylamino group, wherein the methyl group, the ethyl group, the isopropyl group, the vinyl group, the ethynyl group, the difluoromethyl group, the methoxy group, the ethoxy group, the isopropoxy group, the amino group, the methylamino group, the dimethylamino group, the ethylamino group or the diethylamino group is optionally substituted with one or more deuterium atoms, halogen, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups; Preferably, R 3 are independently a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 Alkyl, Oxo(=O), C(=O)R e1 、C(=O)NR e1 or S(=O)2R e1 , the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 0-6 Alkyl-3-6 membered cycloalkyl, C 0-6 Alkyl-3-6 membered heterocyclic group, 3-6 membered cycloalkyl-C 1-6 Alkyl, 3-6 membered heterocyclic group-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl; Preferably, R 3 are each independently a hydrogen atom, a deuterium atom, a halogen, CN, a hydroxyl group, a hydroxyethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a cyclopropyl group, a methoxy group, an ethoxy group, a cyclopropyloxy group, an oxo group, a C(═O)R e1 、C(=O)NR e1 or S(=O)2R e1 ; Among them, R e1 is a hydrogen atom, a methyl group, an ethyl group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a cyclopropylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; More preferably, R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group; More preferably, R 2 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group or a methoxy group, wherein the methyl group, the ethyl group or the methoxy group is optionally substituted by one or more halogen groups; More preferably, R 3 It is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, C(═O)CH 3 , C(═O)-cyclopropyl group, C(═O)N(CH 3 ) 2 or S(═O) 2-cyclopropyl group.

6. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In Formula I, X1 and X2 are each independently absent or each independently NR 1a ,-C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2; Preferably, X1 is absent or is NR 1a ,-C(R 2a )(R 3a )-or O; Preferably, X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2; Among them, R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl is optionally substituted with one or more R'; R 3a For hydrogen atoms, deuterium atoms, halogens, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino, the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino is optionally substituted by one or more R′; Preferably, R 1a , R 2a Each is independently a hydrogen atom, a deuterium atom, F, Cl, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group; or R 3 and R 1a Together with the atoms to which it is attached, it forms a pyrrole, imidazole, thiazole, oxazole, isothiazole, isoxazole or pyrazole; Preferably, R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy; Or, R 2a and R 3a Together with the attached C atom, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by one or more R′; Or, R 2a and R 3a together with the attached C atom form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl being optionally substituted with one or more R′; Or, R 2a and R 3a Together with the attached C atom it forms a cyclopropyl, cyclobutyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, oxirane or oxetanyl group being optionally substituted by one or more halogen, methyl or hydroxyl groups.

7. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: In Formula I, R 4 For R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered cycloalkyl, wherein R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, (R 30 ) p NY(R 20 ) p -C 0-4 Alkyl-4-7 membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-5-6 membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 Alkyl-4-7 membered cycloalkyl is optionally substituted with one or more R'; or, R 4 for Preferably, R 4 Selected from More preferably, R 4 for Most preferably, R 4 Selected from Among them, W 1 is none, O or NH; Y is N or C; Y 1 Not present or N or C; Y 2 , Y 3 Each independently is NR 70 , N, CR 70 , O or S; R 70 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen; q1 or q2 are each independently 1, 2 or 3; Further optionally, R 30 Each is independently a hydrogen atom, a deuterium atom, an amino group, a C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen; Preferably, R 30 each independently represents a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group, wherein the amino group, the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the difluoromethyl group, the difluoroethyl group, the trifluoroethyl group or the hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms; Or, two R 30 Together with the atoms to which it is attached, it forms azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl are optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or halogen; Preferably, R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 alkyl-3-12 membered heterocyclic group or oxo (=O), the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 0-2 Alkyl-3-12 membered cycloalkyl or C 0-2 The alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substitution; Preferably, R 20 , R 40 , R 50 , R 60 each independently represents a hydrogen atom, a deuterium atom, F, Cl, Br, CN, hydroxyl, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy or oxo, and the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy or ethoxy is optionally substituted by one or more halogen, methyl or deuterium atoms; Or, two R 20 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen; Or, R 20 and R 50 Together with the atoms to which they are attached they form azetidinyl, azetidinyl, azetidinyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the azetidinyl, azetidinyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano; Or, R 40 and R 60 Together with the atoms to which they are attached, they form azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, which are optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano; More preferably, R 30 Each is independently a hydrogen atom, amino, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl; More preferably, R 20 , R 40 , R 50 , R 60 Each is independently a hydrogen atom, a deuterium atom, F, Cl, Br, CN, a hydroxyl group, an amino group, a methyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a deuterated methyl group or an oxo group.

8. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof, wherein: The compound is selected from the structural formula shown in formula II, formula III, formula IV, formula V, formula VI or formula VII Wherein, in Formula II, A, M, X1, X2, L2, R 1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,Y,m,n,t,p,U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 The definition as described in any one of claims 1 to 9; Wherein, in Formula III, A, M, X1, X2, L2, R 1 , R 2 , R 3 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,Y,m,n,t,p,U 1 , U 2 or U 6 The definition as described in any one of claims 1 to 9; Wherein, in Formula IV, X1, X2, L2, R 1 , R 2 , R 5 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,m,p,U 1 , U 2 or U 6 The definition as described in any one of claims 1 to 9; U 8 is N, Cr 1 , O, S or C(=O); U 9 Does not exist or is N, CR 1 , O, S or C(=O); U 11 is N, Cr 1 , O, S or C(=O); Wherein, in Formula V, Formula VI or Formula VII, Y, X1, X2, L2, R 1 , R 2 , R 20 , R 30 , R 40 , R 50 , R 60 , W 1 ,m,p,U 1 , U 2 or U 6 The definition as described in any one of claims 1 to 9; U 9 Does not exist or is N, CR 1 , O, S or C(=O); U 10 is CR 1′ ; U 11 is N, Cr 1 , O, S or C(=O); U 12 -N(R 3a′ )-、-C(R 3a′ )=C(R 3a′ )-; q is 1, 2, or 3; R 1′ For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R′; Preferably, R 1′ is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuterium, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropyloxy or oxo; Wherein, in Formula IV, Formula V, Formula VI or Formula VII, R 3a′ for hydrogen atoms, deuterium atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, OR e1 , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′; Preferably, R 3a′ is a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, the ethyl group, the propyl group, the vinyl group, the ethynyl group, the cyclopropyl group, the cyclobutyl group, the oxirane group, the oxirane group, the aziridine group, the azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, a fluorine group, a chlorine group, a bromine group, a CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group; Preferably, R 3b′ For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3-12 membered cycloalkyl, C 0-6 Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more R′; Preferably, R 3b′ It is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, a methyl group, an ethyl group, a propyl group, a trideuterium methyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group are optionally substituted by one or more of the following groups: a deuterium atom, fluorine, chlorine, bromine, CN, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, an oxo group.

9. The aminoheteroaryl macrocyclic compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof, wherein: The compound represented by any one of formula I to VII is selected from the following compounds:

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

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

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