Amino heteroaryl macrocyclic compounds as well as preparation method therefor and use thereof

Abstract

Amino heteroaryl macrocyclic compounds, a preparation method therefor and the use thereof. The structure of the amino heteroaryl macrocyclic compounds is shown as formula I: (I), wherein the definitions of A, M, E, X1, X2, L2, R1, R2, R3, R4, m, n and t are as described in the description. The amino heteroaryl macrocyclic compounds have efficient and highly selective inhibitory effects on epidermal growth factor receptors (EGFRs), and thus can be used for treating related diseases induced by EGFR anomalies, especially in the treatment of cancer diseases.

Description

Aminoheteroaryl macrocyclic compound and its preparation method and application 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, leading to 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 extracellularly, the receptor undergoes homotypic or heterotypic dimerization and autophosphorylation, activating downstream signaling pathways and ultimately promoting cell growth, proliferation, and division. Overexpression (upregulation) or overactivity (amplification or mutation) of EGFR has been linked to numerous 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 led to the development of targeted therapies using small-molecule EGFR inhibitors. In non-small cell lung cancer (NSCLC), 50%-80% of patients harbor EGFR mutations (primarily the in-frame deletion mutation Ex19Del in exon 19 and the arginine-to-lysine substitution L858R at position 858 in exon 21, both of which are also known as EGFR-sensitizing mutations). Currently, three generations of EGFR small-molecule inhibitors are approved for the treatment of patients with EGFR-mutated NSCLC. First- and second-generation EGFR inhibitors, such as Iressa, Tarceva, afatinib, and dacomitinib, have achieved significant success in the treatment of NSCLC. However, these inhibitors can be associated with significant clinical side effects such as rash and diarrhea, and patients can develop drug resistance after one year of use. Clinical data indicate that approximately 50% of patients develop acquired resistance due to the T790M (methionine-to-threonine substitution at position 790 in exon 20) mutation.

[0005] Third-generation EGFR inhibitors, such as osimertinib, are irreversible inhibitors that covalently bind to C797, significantly enhancing its activity. They can be used as second-line treatment for patients with the EGFR T790M mutation after treatment with first- and second-generation EGFR inhibitors, and as first-line treatment for patients with EGFR-sensitive mutations. However, osimertinib, as a second-line treatment for patients with the EGFR T790M mutation, inevitably develops the C797X triple resistance mutation (mutation of cysteine ​​at position 797 in exon 20 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 developed 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. In the FLAURA study, a study of 91 patients with osimertinib-resistant disease who progressed on osimertinib found that 7% of patients had C797S dual resistance mutations.

[0008] For patients with EGFR-sensitizing mutations, the recommended first-line treatment is a third-generation EGFR inhibitor such as osimertinib. However, after a period of osimertinib use, the C797X double-resistance mutation inevitably develops. Currently, there are no approved treatments for patients with the C797X mutation, representing an unmet clinical need.

[0009] In addition to the common sensitive mutations Ex19Del and L858R, approximately 4-10% of lung cancer patients have EGFR exon 20 insertion mutations, of which most 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 was 28%, and the DOR was 17.5 months. However, on October 2, 2023, Takeda Pharmaceutical's official website announced that because the phase III randomized controlled trial EXCLAIM-2 comparing mobocertinib with platinum-containing chemotherapy did not meet the preset clinical endpoints, it proactively withdrew mobocertinib from the market worldwide. In addition, other marketed EGFR inhibitors are resistant to EGFR exon 20 insertion mutations and have poor efficacy, with an ORR of 0-28%. Amivantamab, a dual-antibody for EGFR / c-Met, 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 address the deficiencies of the prior art, the present invention aims to provide an aminoheteroaryl macrocyclic compound and a preparation method and application thereof, wherein 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] Wherein, in Formula I,

[0015] Ring A 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;

[0016] The E ring is a 5-12 membered heteroaryl, a 6-12 membered aryl or a 3-12 membered heterocyclic group, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl or the 3-12 membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0017] The M ring is a 5-12 membered heteroaryl, a 6-12 membered aryl, a 3-12 membered heterocyclyl, a 3-12 membered cycloalkyl or a 3-12 membered cycloalkenyl, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl, the 3-12 membered heterocyclyl, the 3-12 membered cycloalkyl or the 3-12 membered cycloalkenyl is connected to the A ring and X2 through two different atoms;

[0018] 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 Heteroalkenylene is optionally substituted by one or more identical or different R 5 replace;

[0019] 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 );

[0020] 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 1-6Alkyl, 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';

[0021] 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-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)Re1 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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0022] Or two R 2 together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-12 membered heterocyclyl, a 5-14 membered heteroaryl, or a 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, which is optionally substituted with one or more R′;

[0023] R 4 for

[0024] 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-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 )Re1 、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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0025] 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, which is optionally substituted with one or more R′;

[0026] R 1a 、R 2a Each independently does not exist or is 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';

[0027] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0028] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0029] 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';

[0030] 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′;

[0031] or R 2 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′;

[0032] 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′;

[0033] 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 Rf2 、P(=O)2R f1 R f2 、P(=O)OR f2 or oxo (=O);

[0034] 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″;

[0035] 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 with 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 ;

[0036] 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 with 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 ;

[0037] R″ is a deuterium atom, 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 、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);

[0038] 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;

[0039] W 1 None, O, or NR g1 ;

[0040] Y is N or C;

[0041] represents a single bond or a double bond;

[0042] 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 with one or more R′;

[0043] 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 with one or more R';

[0044] Or, two R 20Together 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 with one or more R′;

[0045] 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 with one or more R′;

[0046] 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 with one or more R′;

[0047] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0048] p is each independently 1 or 2.

[0049] 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

[0050] Wherein, in Formula I,

[0051] Ring A 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;

[0052] The E ring is a 5-12 membered heteroaryl, a 6-12 membered aryl or a 3-12 membered heterocyclic group, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl or the 3-12 membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0053] The M ring is a 5-12 membered heteroaryl, a 6-12 membered aryl, a 3-12 membered heterocyclyl, a 3-12 membered cycloalkyl or a 3-12 membered cycloalkenyl, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl, the 3-12 membered heterocyclyl, the 3-12 membered cycloalkyl or the 3-12 membered cycloalkenyl is connected to the A ring and X2 through two different atoms;

[0054] 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 Heteroalkenylene is optionally substituted by one or more identical or different R 5 replace;

[0055] 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 );

[0056] 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';

[0057] 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 0-6Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic-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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0058] Or two R 2 together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-12 membered heterocyclyl, a 5-14 membered heteroaryl, or a 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, which is optionally substituted with one or more R′;

[0059] R 4 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, said 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';

[0060] 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-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, 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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0061] 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, which is optionally substituted with one or more R′;

[0062] R 1a 、R 2a Each independently does not exist or is 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';

[0063] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0064] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0065] 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)Re1 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';

[0066] 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′;

[0067] 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′;

[0068] 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′;

[0069] 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)(=W1 )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);

[0070] 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″;

[0071] 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 with 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 ;

[0072] 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 with 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 ;

[0073] 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 Rg2 、P(=O)OR g2 or oxo (=O);

[0074] 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;

[0075] W 1 None, O, or NR g1 ;

[0076] Y does not exist or is N or C;

[0077] 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 with one or more R′;

[0078] 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 0-6Alkyl-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 with one or more R′;

[0079] 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 with one or more R′;

[0080] 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 with one or more R′;

[0081] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0082] p is each independently 1 or 2.

[0083] In certain embodiments, in Formula I,

[0084] Ring A 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;

[0085] The E ring is a 5-12 membered heteroaryl, a 6-12 membered aryl or a 3-12 membered heterocyclic group, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl or the 3-12 membered heterocyclic group is connected to the N atom of NH and X1 through two different atoms, respectively;

[0086] The M ring is a 5-12 membered heteroaryl, a 6-12 membered aryl, a 3-12 membered heterocyclyl, a 3-12 membered cycloalkyl or a 3-12 membered cycloalkenyl, wherein the 5-12 membered heteroaryl, the 6-12 membered aryl, the 3-12 membered heterocyclyl, the 3-12 membered cycloalkyl or the 3-12 membered cycloalkenyl is connected to the A ring and X2 through two different atoms;

[0087] L2 is C1-6 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 Heteroalkenylene is optionally substituted by one or more identical or different R 5 replace;

[0088] 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 );

[0089] 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';

[0090] R 2 、R 3 are independently hydrogen, deuterium, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6Alkyl-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-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 0-6Alkyl-5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0091] Or two R 2 together with the atoms to which they are attached, form a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-12 membered heterocyclyl, a 5-14 membered heteroaryl, or a 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, which is optionally substituted with one or more R′;

[0092] R 4 for

[0093] 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-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 NRe1 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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0094] 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, which is optionally substituted with one or more R′;

[0095] R 1a 、R 2a Each independently does not exist or is 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 e1R 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';

[0096] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0097] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0098] 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 Re2 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';

[0099] 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′;

[0100] 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′;

[0101] 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′;

[0102] 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);

[0103] 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 C1-6 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″;

[0104] 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 with 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 ;

[0105] 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 with 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 ;

[0106] 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 Rg2 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);

[0107] 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;

[0108] W 1 None, O, or NR g1 ;

[0109] 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;

[0110] 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, C 2-6 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 with one or more R';

[0111] R20 、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 with one or more R';

[0112] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0113] p is each independently 1 or 2.

[0114] In certain embodiments, the compound of formula I is further represented by formula II:

[0115] 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;

[0116] --- means no or single key;

[0117] U 1 Not present or N or CH;

[0118] U 2 Not present or N or CH;

[0119] U 3 N, C, NR100 , O, S or C(=O);

[0120] U 4 and U 5 are each independently N or C, and U 4 and U 5 Not all N at the same time;

[0121] U 6 N or CH;

[0122] U 7 C, N, NR 200 ,O,S,C(=O),C(=O)O,C(=O)NR 300 , OC(=O) or NR 300 C(=O);

[0123] 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;

[0124] 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;

[0125] 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;

[0126] When Y is C, the M ring is pyridine, pyrimidine, pyridone, pyridazine, oxazole, thiazole, imidazole, pyrroletriazole or pyridine N-oxide.

[0127] In certain embodiments, the compound of Formula I is further represented by Formula III:

[0128] Among them, A, M, X1, X2, L2, R 1 、R 2 、R 3 、R20 、R 30 、R 40 、R 50 、R 60 、W 1 ,Y,m,n,t,p are defined as above;

[0129] U 1 、U 2 or U 6 are each independently N or CH.

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

[0131] 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;

[0132] 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) of C 2-6 Heteroalkenylene is optionally substituted by 2 or more identical or different R 5 replace;

[0133] At least two independent 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, which is optionally substituted with one or more R′;

[0134] U 1 、U 2 or U 6 are each independently N or CH;

[0135] U 8 N, CR 1 , O, S or C(=O);

[0136] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0137] U 11 N, CR 1 , O, S or C(=O);

[0138] 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 with one or more R';

[0139] 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 with one or more R';

[0140] R 5 , R′, R e1 The definition of is as described above.

[0141] In certain embodiments, the compound of Formula I is further represented by Formula V:

[0142] 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;

[0143] 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) of C 2-6 Heteroalkenylene is optionally substituted by one or more identical or different R 5 replace;

[0144] U 1 、U 2 or U 6 are each independently N or CH;

[0145] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0146] U 10 CR 1′ ;

[0147] U 11 N, CR 1 , O, S or C(=O);

[0148] R1′ 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';

[0149] 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 with one or more R';

[0150] 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 with one or more R';

[0151] R 5 , R′, R e1 The definition of is as described above.

[0152] In certain embodiments, in Formula I,

[0153] 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;

[0154] Preferably, the E ring is

[0155] More preferably, the E ring is selected from

[0156] Most preferably, the E ring is selected from

[0157] 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.

[0158] In certain embodiments, Ring A is a 5-6 membered heteroaryl;

[0159] Preferably, Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole;

[0160] More preferably, the A ring is selected from the following groups:

[0161] * a Indicates the connection site with the N atom of NH, * b Indicates the site of attachment to the M loop.

[0162] In certain embodiments, the M ring is a 5-6 membered heteroaryl or benzene;

[0163] Preferably, the M ring is pyridine, pyrimidine, pyridazine, imidazole, pyrazole, thiazole, oxazole, triazole, benzene or pyridine N-oxide;

[0164] More 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 attachment to X2.

[0165] 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 1-6Alkenylene or containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) and other atoms of C 1-6 Heteroalkylene is optionally substituted with one or more identical or different R 5 replace;

[0166] Preferably, 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;

[0167] 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;

[0168] 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';

[0169] 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 with one or more R';

[0170] 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'

[0171] Preferably, X1 is absent or NR 1a 、-C(R2a )(R 3a )- or O;

[0172] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0173] 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;

[0174] 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;

[0175] or R 2a and R 3a Together with the attached C atom, they form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, which is optionally substituted with one or more R's.

[0176] In certain embodiments, R 1 are independently hydrogen, deuterium, 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';

[0177] Preferably, R 1 are each independently 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;

[0178] More preferably, R 1Each is independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

[0179] In certain embodiments, R 2 are independently hydrogen, deuterium, 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-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;

[0180] Preferably, R 2 Each 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, ethyl group, 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.

[0181] In certain embodiments, R 3 are independently hydrogen, deuterium, halogen, CN, C 1-6Alkyl, 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-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-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0182] 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 ;

[0183] 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;

[0184] R e1is 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;

[0185] 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 an S(═O) 2-cyclopropyl group.

[0186] In certain embodiments, R 4 for

[0187] In certain embodiments, R 4 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, said 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 -C0-4 Alkyl-4-7 membered cycloalkyl is optionally substituted with one or more R';

[0188] Preferably, R 4 Selected from

[0189] Wherein, Y is absent or is N or C;

[0190] Y 1 Not present or N or C;

[0191] Y 2 、Y 3 Each independently is NR 70 , N, CR 70 , O or S;

[0192] W 1 None, O, or NR g1 ;

[0193] R 20 、R 30 、R 40 、R 50 、R 60 The definition of is as described above;

[0194] 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;

[0195] q1 or q2 are each independently 1, 2 or 3;

[0196] Or, two R 20 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0197] Or, two R 30Together with the atoms to which it is attached, they form azetidinyl, azepentyl, or azetidinyl, wherein the azetidinyl, azepentyl, or azetidinyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or halogen;

[0198] Or, R 20 and R 50 Together with the atoms to which they are attached they form azetidinyl, azepentyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl, said azetidinyl, azepentyl, azetidinyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano;

[0199] Or, R 40 and R 60 Together with the atoms to which they are attached, they form azetidinyl, azepentyl, or azetidinyl, wherein the azetidinyl, azepentyl, or azetidinyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, or cyano groups;

[0200] More preferably, R 4 Selected from

[0201] 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 0-2 Alkyl-3-12 membered heterocyclic group or C 1-6 Alkoxy is optionally substituted with one or more R';

[0202] 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 C1-6 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;

[0203] 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, said 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0204] 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;

[0205] 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'.

[0206] 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.

[0207] 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 1-6Alkoxy, 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 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substituted;

[0208] 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.

[0209] 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 0-2 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;

[0210] Preferably, R 30Each 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.

[0211] 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;

[0212] Preferably, W 1 It is O.

[0213] 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;

[0214] Preferably, Y is N.

[0215] In certain embodiments,

[0216] 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, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0217] R 3b′ 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 oxetane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an oxetane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0218] R 1′It 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.

[0219] In certain embodiments, the compound further has the structure shown in Formula VI:

[0220] in,

[0221] 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) 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 ) of C 1-6 Heteroalkylene, containing 1-3 selected from N, O, S, C (= O), S (= O) (= W 1 ) of C 2-6 Heteroalkenylene is optionally substituted by one or more identical or different R 5 replace;

[0222] 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-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)NRe1 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-C 1-6 Alkyl, 6-10 membered aryl-C 1-6 Alkyl, 5-10 membered heteroaryl-C 1-6 Alkyl is optionally substituted with one or more R';

[0223] 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, which is optionally substituted with one or more R′;

[0224] q is 1, 2, or 3;

[0225] 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,p are defined as above;

[0226] Preferably, 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;

[0227] 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';

[0228] 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, said 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0229] 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 hydrogen, deuterium, halogen, CN, hydroxyl, 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;

[0230] 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, said 3-6 membered cycloalkyl, 3-7 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0231] 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, said 3-6 membered cycloalkyl, 3-7 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0232] 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, said 3-6 membered cycloalkyl, 3-7 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0233] 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, said 3-6 membered cycloalkyl, 3-7 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0234] 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, said 3-6 membered cycloalkyl, 3-7 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0235] 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's.

[0236] In certain embodiments, the compound further has the structure shown in Formula VII:

[0237] Among them, U 12 -N(R 3a′ )-、-C(R 3a′ )=C(R 3a′ )-;

[0238] 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′ The definition of is as mentioned above;

[0239] In certain embodiments, in Formula I:

[0240] Ring A is a 5-6 membered heteroaryl group;

[0241] The M ring is a 5-6 membered heteroaryl group or benzene;

[0242] The E ring is

[0243] 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 Heteroalkylene is optionally substituted with one or more identical or different R 5 replace;

[0244] 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;

[0245] R 1 are each independently 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;

[0246] R 2 are independently hydrogen, deuterium, 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-C 1-6 Alkyl or oxo (=O), the C 1-6 Alkyl, halogenated C1-6 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;

[0247] R 3 are independently hydrogen, deuterium, 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-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-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0248] R 4 for

[0249] 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';

[0250] 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, said 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0251] 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';

[0252] 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 with one or more R';

[0253] 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;

[0254] 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′;

[0255] 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;

[0256] W 1 is none, O or NH;

[0257] 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;

[0258] --- means no or single key;

[0259] U 1 Not present or N or C;

[0260] U 2 Not present or N or C;

[0261] U 3 is C or C(=O);

[0262] U 4 and U 5 Each independently is C;

[0263] U 6 N or CH;

[0264] U 7 is C, N, N-methyl, N-ethyl or N-cyclopropyl;

[0265] 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, C1-6 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 is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substituted;

[0266] 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;

[0267] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0268] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0269] p is each independently 1 or 2.

[0270] In certain embodiments, in Formula I:

[0271] Ring A is a 5-6 membered heteroaryl group;

[0272] The M ring is a 5-6 membered heteroaryl group or benzene;

[0273] The E ring is

[0274] 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 C1-6 Heteroalkylene is optionally substituted with one or more identical or different R 5 replace;

[0275] 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;

[0276] R 1 are each independently 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;

[0277] R 2 are independently hydrogen, deuterium, 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-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;

[0278] R3 are independently hydrogen, deuterium, 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-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-C 1-6 The alkyl group is optionally substituted with one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

[0279] R 4 for

[0280] 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';

[0281] 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, said 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0282] 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';

[0283] 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 with one or more R';

[0284] 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;

[0285] 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′;

[0286] 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;

[0287] W 1 is none, O or NH;

[0288] Y is N or C;

[0289] --- means no or single key;

[0290] U 1 Not present or N or C;

[0291] U 2 Not present or N or C;

[0292] U 3 is C or C(=O);

[0293] U 4 and U 5 Each independently is C;

[0294] U 6 N or CH;

[0295] U 7 is C, N, N-methyl, N-ethyl or N-cyclopropyl;

[0296] 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 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substituted;

[0297] 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 0-2Alkyl-3-12 membered heterocyclyl is optionally substituted by one or more deuterium atoms, CN, hydroxyl or halogen;

[0298] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0299] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0300] p is each independently 1 or 2.

[0301] In certain embodiments, in Formula VI or Formula VII,

[0302] 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 Heteroalkylene is optionally substituted with one or more identical or different R 5 replace;

[0303] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0304] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0305] R 2 are independently hydrogen, deuterium, 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 0-6Alkyl-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-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;

[0306] R 5 are independently hydrogen, deuterium, 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';

[0307] 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, said 3-6 membered cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl or 3-6 membered cycloalkenyl being optionally substituted with one or more R′;

[0308] 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';

[0309] 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 with one or more R';

[0310] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0311] 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, said 3-12 membered heterocyclyl or 5-12 membered heteroaryl being optionally substituted with one or more R′;

[0312] 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′;

[0313] 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′;

[0314] 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′;

[0315] Y is N or C;

[0316] W 1is none, O or NH;

[0317] U 1 N or C;

[0318] U 2 N or C;

[0319] U 6 N or CH;

[0320] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0321] U 10 CR 1′ ;

[0322] U 11 N, CR 1 , O, S or C(=O);

[0323] U 12 -N(R 3a′ )-、-C(R 3a′ )=C(R 3a′ )-;

[0324] 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 Alkyl-3-12 membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 Alkyl or halogen substituted;

[0325] 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 with one or more R′;

[0326] 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;

[0327] 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 with one or more R′;

[0328] 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 with one or more R';

[0329] 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 with one or more R';

[0330] R 1′ For hydrogen atoms, deuterium atoms, halogens, CN, NO2, C 1-6Alkyl, 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';

[0331] m is 0, 1, 2, 3, or 4;

[0332] p is each independently 1 or 2;

[0333] q is 1, 2, or 3.

[0334] In other specific embodiments,

[0335] Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole;

[0336] Ring M is pyridine, pyrimidine, pyridazine, imidazole, pyrazole, thiazole, oxazole, triazole, benzene or pyridine N-oxide;

[0337] The E ring is

[0338] 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;

[0339] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0340] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0341] 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;

[0342] 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;

[0343] R 3 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 an S(═O) 2-cyclopropyl group;

[0344] R 4 for

[0345] 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;

[0346] Or two R 5 together with the atoms to which they are attached, form a 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′;

[0347] 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;

[0348] 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;

[0349] or R 2a and R 3aTogether with the attached C atom, they form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, cyclopentylcyclohexyl, oxirane or oxetanyl group being optionally substituted with one or more R′;

[0350] W 1 is none, O or NH;

[0351] 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;

[0352] --- means no or single key;

[0353] U 1 N or C;

[0354] U 2 N or C;

[0355] U 3 、U 4 and U 5 Each independently is C;

[0356] U 6 N or CH;

[0357] U 7 is C;

[0358] 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, wherein the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, or ethoxy group is optionally substituted with one or more halogen, methyl, or deuterium atoms;

[0359] 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;

[0360] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0361] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0362] p is each independently 1 or 2.

[0363] In other specific embodiments, in Formula IV,

[0364] 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;

[0365] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0366] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0367] 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;

[0368] 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;

[0369] R 5is 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;

[0370] At least two R 5 together with the atoms to which they are attached, form a 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′;

[0371] 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;

[0372] 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;

[0373] or R 2a and R 3a together with the attached C atom, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group being optionally substituted with one or more R′;

[0374] W 1 is none, O or NH;

[0375] U 1 N or C;

[0376] U 2 N or C;

[0377] U 6 N or CH;

[0378] U 8 N, CR 1 , O, S or C(=O);

[0379] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0380] U 11 N, CR 1 , O, S or C(=O);

[0381] 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, wherein the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, or ethoxy group is optionally substituted with one or more halogen, methyl, or deuterium atoms;

[0382] 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;

[0383] 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, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0384] R 3b′ 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 oxetane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an oxetane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0385] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0386] m is 0, 1, 2, 3, or 4;

[0387] p is each independently 1 or 2.

[0388] In other specific embodiments, in Formula V,

[0389] 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;

[0390] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0391] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0392] 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;

[0393] 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;

[0394] R 5is 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;

[0395] 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;

[0396] 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;

[0397] or R 2a and R 3a together with the attached C atom, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group being optionally substituted with one or more R′;

[0398] W 1 is none, O or NH;

[0399] U 1 N or C;

[0400] U 2 N or C;

[0401] U 6 N or CH;

[0402] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0403] U 10 CR 1′ ;

[0404] U 11 N, CR 1 , O, S or C(=O);

[0405] R 20 、R 40 、R 50 、R 60each 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, wherein the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, or ethoxy group is optionally substituted with one or more halogen, methyl, or deuterium atoms;

[0406] 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;

[0407] 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, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0408] R 3b′ 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 oxetane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an oxetane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0409] 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;

[0410] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0411] m is 0, 1, 2, 3, or 4;

[0412] p is each independently 1 or 2.

[0413] In other specific embodiments, in Formula VI or Formula VII,

[0414] 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;

[0415] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0416] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0417] 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;

[0418] R 5each 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;

[0419] 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, 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′;

[0420] 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;

[0421] 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;

[0422] or R 2a and R 3a together with the attached C atom, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group being optionally substituted with one or more R′;

[0423] Y is N or C;

[0424] W 1 is none, O or NH;

[0425] U 1 N or C;

[0426] U 2 N or C;

[0427] U 6 N or CH;

[0428] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0429] U10 CR 1′ ;

[0430] U 11 N, CR 1 , O, S or C(=O);

[0431] U 12 -N(R 3a′ )-、-C(R 3a′ )=C(R 3a′ )-;

[0432] 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, wherein the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, or ethoxy group is optionally substituted with one or more halogen, methyl, or deuterium atoms;

[0433] 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;

[0434] Or, two R 20 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0435] 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, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0436] R 3b′ 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 oxetane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an oxetane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0437] 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;

[0438] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0439] m is 0, 1, 2, 3, or 4;

[0440] p is each independently 1 or 2;

[0441] q is 1, 2, or 3.

[0442] In some further specific embodiments,

[0443] Ring A is selected from the following groups:

[0444] * a Indicates the connection site with the N atom of NH, * bIndicates the site of connection with the M loop;

[0445] 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;

[0446] The E ring is

[0447] 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;

[0448] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0449] X2 is -C(R 2a )(R 3a )-, O, C(=O) or S(=O)2;

[0450] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0451] R 2 are each 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;

[0452] 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;

[0453] R 4 for

[0454] 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;

[0455] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane group is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl or cyclopropyl groups;

[0456] 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;

[0457] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0458] 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;

[0459] U 1 N or C;

[0460] U 2 N or C;

[0461] U 3 、U 4 and U 5 Each independently is C;

[0462] U 6 N or CH;

[0463] U 7 is C;

[0464] 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;

[0465] R 30 Each is independently a hydrogen atom, amino, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl;

[0466] W 1 is O;

[0467] Y is N or C;

[0468] --- or -- means no or single key;

[0469] m, n, and t are each independently 0, 1, 2, 3, or 4;

[0470] p is each independently 1 or 2.

[0471] In some further specific embodiments,

[0472] Ring A is selected from the following groups:

[0473] * a Indicates the connection site with the N atom of NH, * b Indicates the site of connection with the M loop;

[0474] 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;

[0475] The E ring is selected from

[0476] 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;

[0477] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0478] X2 is -C(R 2a )(R 3a )-, O, C(=O) or S(=O)2;

[0479] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0480] R 2 are each 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;

[0481] 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;

[0482] R 4 Selected from

[0483] 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;

[0484] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane group is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl or cyclopropyl groups;

[0485] 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;

[0486] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0487] 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;

[0488] m, n, and t are each independently 0, 1, 2, 3, or 4.

[0489] In some further embodiments, in Formula VI or Formula VII,

[0490] L2 is Among them, R 5a 、R 5b 、R 5c 、R 5a′ 、R 5b′ 、R 5c′ Each independently is R 5 ; R 5 is a hydrogen atom, a deuterium atom, F, Cl, Br, 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;

[0491] Or, R 5a and R5a′ 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′;

[0492] 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′;

[0493] 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′;

[0494] 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′;

[0495] 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′;

[0496] Or, R 5b 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′;

[0497] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0498] X2 is -C(R 2a )(R 3a )-, O, C(=O), S(=O) or S(=O)2;

[0499] 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;

[0500] 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;

[0501] 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, 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′;

[0502] 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;

[0503] 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;

[0504] or R 2a and R 3a together with the attached C atom, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane or oxetanyl group being optionally substituted with one or more R′;

[0505] Y is N or C;

[0506] W 1 is none, O or NH;

[0507] U 1 N or C;

[0508] U 2 N or C;

[0509] U 6 N or CH;

[0510] U 9 Does not exist or is N, CR 1 , O, S or C(=O);

[0511] U 10 CR 1′ ;

[0512] U 11 N, CR 1 , O, S or C(=O);

[0513] U 12 -N(R 3a′ )-、-C(R 3a′ )=C(R 3a′ )-;

[0514] R 20 、R 40 、R 50 、R 60each 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, wherein the amino, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, or ethoxy group is optionally substituted with one or more halogen, methyl, or deuterium atoms;

[0515] 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;

[0516] Or, two R 20 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen;

[0517] 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, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0518] R 3b′ 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 oxetane group, an aziridine group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxirane group, an oxetane group, an aziridine group, an azetidinyl group is optionally substituted with 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;

[0519] 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;

[0520] R′ is a deuterium atom, halogen, CN, hydroxy, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyloxy or oxo;

[0521] m is 0, 1, 2, 3, or 4;

[0522] p is each independently 1 or 2;

[0523] q is 1, 2, or 3.

[0524] In some further specific embodiments,

[0525] Ring A is selected from the following groups: * a Indicates the connection site with the N atom of NH, * b Indicates the site of connection with the M loop;

[0526] 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;

[0527] The E ring is selected from

[0528] 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;

[0529] X1 does not exist or is NR 1a 、-C(R 2a )(R 3a )- or O;

[0530] X2 is -C(R 2a)(R 3a )-, O, C(=O) or S(=O)2;

[0531] R 1 are each independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group;

[0532] R 2 are each 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;

[0533] 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;

[0534] R 4 Selected from

[0535] 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;

[0536] Or two R 5 Together with the atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl or oxetane group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or oxetane group is optionally substituted with one or more deuterium atoms, halogen, methyl, ethyl or cyclopropyl groups;

[0537] 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;

[0538] R 3a is a hydrogen atom, F, Cl, Br, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy or isopropoxy;

[0539] 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;

[0540] m, n, and t are each independently 0, 1, 2, 3, or 4.

[0541] In some more specific embodiments, the compounds represented by Formulas I to V are selected from the following compounds:

[0542] In a second aspect, in certain embodiments, the present invention provides a method for preparing a compound of formula II, comprising the following reaction steps:

[0543] (1) Compound II-1 and Compound II-2 undergo a coupling reaction to form Compound II-3;

[0544] (2) Compound II-3 and compound II-4 undergo a coupling reaction to form compound II-5;

[0545] (3) deprotection of compound II-5 to form compound II-6;

[0546] (4) Compound II-6 undergoes a Mitsunobu reaction to form a compound represented by Formula II;

[0547] 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 、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.

[0548] In certain embodiments, the present invention provides a method for preparing a compound of formula III, comprising the following reaction steps:

[0549] (1) Compound III-1 and compound III-2 undergo a coupling reaction to form compound III-3;

[0550] (2) Compound III-3 undergoes a coupling reaction with compound II-4 to form compound III-5;

[0551] (3) deprotection of compound III-5 to form compound III-6;

[0552] (4) Compound III-6 undergoes a Mitsunobu reaction to form a compound represented by Formula III;

[0553] 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;

[0554] G is a protecting group, and the protecting group is PMB, SEM, methyl, Boc, Cbz, etc.

[0555] In certain embodiments, the present invention provides a method for preparing a compound of formula IV, comprising the following reaction steps:

[0556] (1) Compound IV-1 and compound IV-2 undergo a coupling reaction to form compound IV-3;

[0557] (2) Compound IV-3 and compound IV-4 undergo a coupling reaction to form compound IV-5;

[0558] (3) deprotection of compound IV-5 to form compound IV-6;

[0559] (4) Compound IV-6 undergoes a Mitsunobu reaction to form a compound represented by Formula IV;

[0560] 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.

[0561] In certain embodiments, the present invention provides a method for preparing a compound of formula V, comprising the following reaction steps:

[0562] (1) Compound V-1 and Compound V-2 undergo a coupling reaction to form Compound V-3;

[0563] (2) Compound V-3 and Compound V-4 undergo a coupling reaction to form Compound V-5;

[0564] (3) deprotection of compound V-5 to form compound V-6;

[0565] (4) Compound V-6 undergoes a Mitsunobu reaction to form a compound represented by Formula V;

[0566] 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 、R 3a′ 、R 3b′ The definitions of , m, and p are as described above.

[0567] In certain embodiments, the present invention provides a method for preparing a compound of formula VII, comprising the following reaction steps:

[0568] (1) Compound VII-1 and Compound VII-2 undergo a coupling reaction to form Compound VII-3;

[0569] (2) Compound VII-3 and compound VII-4 undergo a coupling reaction to form compound VII-5;

[0570] (3) deprotection of compound VII-5 to form compound VII-6;

[0571] (4) Compound VII-6 undergoes a Mitsunobu reaction to form a compound represented by Formula VII;

[0572] Among them, X1, X2, L2, R 1 、R 2 、R 20 、R 30 、R 40 、R50 、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.

[0573] In certain embodiments, the present invention provides another method for preparing the intermediate VII-3 compound, which comprises the following reaction steps:

[0574] (1) Compound VII-7 undergoes a coupling reaction with compound VII-2 to form compound VII-8;

[0575] (2) Compound VII-8 is iodinated to form compound VII-9;

[0576] (3) Compound VII-9 undergoes a Suzuki coupling reaction with compound VII-10 or VII-11 to form compound VII-12;

[0577] (4) Compound VII-12 is reduced to form compound VII-13;

[0578] (5) protecting the compound VII-13 to form a compound of formula VII-3;

[0579] Among them, X m is X1, or X1 containing a double bond;

[0580] 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.

[0581] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient;

[0582] 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.

[0583] In a fourth aspect, the present invention provides the use of the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate, or a pharmaceutical composition comprising the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient in the treatment of diseases mediated by abnormal EGFR;

[0584] Preferably, the disease is a tumor disease;

[0585] 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.

[0586] In a fifth aspect, the present invention provides a method for treating a tumor in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition.

[0587] The patient is preferably a mammal, and the mammal is preferably a human.

[0588] In certain embodiments, the administration route includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, intracisternal, vaginal, peritoneal, bladder, and nasal administration.

[0589] 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.

[0590] The compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope-labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates or pharmaceutical compositions can be introduced into the body through any suitable route, such as oral administration, intravenous injection, intranasal administration, external application, intramuscular injection, intradermal injection, transdermal administration or subcutaneous administration.

[0591] In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotopically labeled substances, deuterated substances, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions thereof, can be formulated into dosage forms suitable for drug release and administered by injection (e.g., subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, intrathecal, intracardial, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes of administration (e.g., oral, enteral, buccal, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).

[0592] Suitable dosage forms include, but are not limited to, dosage forms for injection such as emulsions, solutions and suspensions, dosage forms for oral administration such as tablets, capsules, pills, dragees, powders and granules, dosage forms for topical or transdermal administration such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, and dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and the preparation methods and processes are well known, for example, as provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0593] In certain embodiments, EGFR abnormality refers to EGFR mutation, EGFR amplification, or EGFR overexpression.

[0594] Preferably, EGFR mutation refers to amino acid deletion, change and / or insertion of other amino acids at any position in the EGFR sequence, generally occurring in intracellular exons 18-21 or extracellular exons 2-16.

[0595] 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.; 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.

[0596] In certain embodiments, the compounds or pharmaceutical compositions of the present invention can be administered simultaneously with one or more other pharmacologically active substances, thereby achieving additive or even synergistic effects in vivo. For example, the compounds of the present invention can be combined with other pharmacologically active substances to form a single pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Additional pharmacologically active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal / diabodies, or ADCs, such as osimertinib, ametinib, vumetinib, befortinib, rizitinib, rieltinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, emtansinetrastuzumab, denatinib, and the like; 2) monoclonal / diabodies or ADCs that are inhibitors of downstream pathways or other pathway targets, such as, but not limited to, MEK, RET, PI3K, mTOR, c-Met, PARP, or mitotic kinase inhibitors (such as CDK4 / 6).Such as: Trametinib, Bimetinib, Selumetinib, Palacitinib, Idranib, Copanlisib, Duvelisib, Alpelisib, Umbralisib, Parsaclisib, Rapamycin, Temsirolimus, Everolimus, Capmatinib, Tepotinib, Saivotinib, Gumetinib, Berretinib, Cabozantinib, Emibetuzumab, Telisotuzumab, Niraparib, Palbociclib, Ribociclib, Abemaciclib, etc. ; 3) Anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) Apoptosis inducers (such as Bcl-2), such as obatoclax, venetoclax, etc.; 5) Chemotherapeutic drugs, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilutamide, finasteride, dexamethasone, aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, carboplatin, Mustine, chlorambucil, cladribine, colchicine, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, daunorubicin, dienestilbestrol, diethylstilbestrol, docetaxel, doxorubicin, adriamycin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, goserelin, teniposide, testosterone, titanocene dichloride, topotecan, tretinoin, vinblastine, hydroxyurea, idarubicin, ifosfamide, irinotecan, letrozole Azoles, leucovorin, pentostatin, mithramycin, procarbazine, raltitrexed, porfibril sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, lomustine, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, triazolam, methyl chloride, topotecan titanocene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0597] In certain embodiments, the compounds provided herein can be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, such as durvalumab; agents that reverse multidrug resistance in tumor cells (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

[0598] In certain embodiments, the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be used concurrently with radiotherapy. In certain embodiments, the compounds provided herein can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of these therapies.

[0599] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0600] It is particularly important to note that similar substitutions and modifications made to the present invention will be obvious to those skilled in the art and are considered to be included in the present invention. It is obvious that relevant persons can modify or appropriately change and combine the methods and applications described herein to implement and apply the technology of the present invention without departing from the content, spirit, and scope of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0601] Unless otherwise specified, the present invention was carried out under conventional conditions or those recommended by the manufacturer. The raw materials or excipients, as well as the reagents or instruments used, for which the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0602] 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.

[0603] --- means no or single key.

[0604] Indicates the junction site.

[0605] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix (C a-b )alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C 1-6 ) Alkyl refers to an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or linear.

[0606] The atoms described in the compounds of the present invention include their isotopes, for example, hydrogen may be deuterium or tritium.

[0607] "Bridged ring" refers to a polycyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The ring atoms may be all carbon atoms or one or more ring atoms may be selected from N, O, S, SO or SO2. 7-10 rings are preferred.

[0608] "Spirocyclic" refers to a polycyclic group in which any two rings share a common carbon atom. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The ring atoms may be all carbon atoms or one or more of the ring atoms may be selected from N, O, S, SO or SO2. Preferably, the ring has 5-10 rings.

[0609] Fused ring: refers to a polycyclic group in which each ring shares two adjacent atoms with other rings in the system.

[0610] According to the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group.

[0611] A cyclic group can be bonded to another group in a variety of ways. If the bonding method is not specified, all possible methods are included. For example, "pyridyl" includes 2-, 3-, or 4-pyridyl, and "thienyl" includes 2- or 3-thienyl.

[0612] "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:

[0613] Deuterium atoms, halogens, cyano groups, nitro groups, azide groups, hydroxyl groups, 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).

[0614] "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.

[0615] "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-.

[0616] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, which can be combined with other groups. Monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups with 3 to 8 members are preferred. Cycloalkyl groups with 3 to 6 members are more preferred. Cycloalkyl groups with 3 to 5 members are more preferred. Polycyclic hydrocarbon groups include linked, spirocyclic, fused, or bridged ring hydrocarbon groups, including but not limited to the following groups:

[0617] "Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond, but does not form a completely conjugated π electron system and can be combined with other groups. Monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctenyl, etc. Preferably, a 3-8 membered cycloalkenyl. More preferably, a 3-6 membered cycloalkenyl. More preferably, a 5-6 membered cycloalkenyl. Polycyclic cycloalkenyls include linked rings, spiro rings, fused rings, or bridged ring cycloalkenyls. Including but not limited to the following groups:

[0618] The cycloalkyl or cycloalkenyl group may be fused with an aryl group, a heteroaryl group or a heterocyclic group, including but not limited to tetrahydronaphthyl, benzocycloheptyl and the like.

[0619] "Alkenyl" refers to a linear, branched or cyclic hydrocarbon group containing one or more carbon-carbon double bonds, including but not limited to ethenyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably C 2-6 More preferably C 2-4 Alkenyl.

[0620] "Heteroalkenyl" refers to an alkenyl group in which a carbon atom is substituted 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.

[0621] "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-.

[0622] "Alkynyl" refers to a linear, branched or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. 2-6 More preferably C 2- 4 alkynyl.

[0623] "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-.

[0624] "Alkenylene" refers to a straight-chain 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.

[0625] "Alkynylene" refers to a straight-chain or branched, divalent alkynyl group, i.e., one hydrogen atom 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.

[0626] "Halogen" refers to fluorine, chlorine, bromine or iodine, with fluorine, chlorine and bromine being preferred.

[0627] "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 groups (e.g., -CF3), and the like.

[0628] "Alkylamino" refers to NH3 substituted by an alkyl group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, etc.

[0629] "Dialkylamino" refers to a group having the structure N(C 1-6 The group of alkyl)2 includes but is not limited to dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino and the like.

[0630] "Aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or unfused aromatic rings, including but not limited to phenyl, naphthyl, and indenyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. Phenyl or naphthyl is more preferred. Phenyl is most preferred.

[0631] "Heterocyclyl" refers to a 4-12 membered non-aromatic monocyclic or polycyclic ring system having ring carbon atoms and 1-4 ring heteroatoms, including saturated rings with only single bonds and unsaturated rings with at least one double bond (C=C, C=N or N=N), but not forming a completely conjugated π electron system. The heteroatoms are independently selected from N, O, S, nitrogen oxide (NO), sulfoxide, S(O)(=NH) and sulfone. Polycyclic ring systems include fused, bridged or spiro ring systems. Examples of monocyclic heterocyclic moieties include, but are not limited to, aziridine, azetidinyl (azetidinyl), oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidine, thiadiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc. Preferred are 4-7 membered heterocyclic groups. More preferred are 4-6 membered heterocyclic groups. Examples of polycyclic heterocyclyl moieties include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-oxa-2-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2 .1]octyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, etc. Examples of unsaturated heterocyclic moieties include, but are not limited to:

[0632] 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:

[0633] 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 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 2-6Heteroalkenyl, 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).

[0634] "Heteroaryl" refers to a substituted or unsubstituted 5- or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or biheteroaromatic ring system containing 1-4 heteroatoms independently selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl, or benzothiazolyl.

[0635] 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:

[0636] Heteroaryl 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 1-10 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).

[0637] "Alkoxy" refers to a straight or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy and other similar groups. 1-8 Alkoxy. More preferably C 1-6 Alkoxy. More preferably C 1-4 Alkoxy.

[0638] "Cycloalkoxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Preferably, C 3-8Cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and other similar groups.

[0639] "Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein the heterocyclyl group is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, pyrrolidinyloxy, oxhexyloxy, piperidinyloxy and other similar groups.

[0640] "Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compound of Formula I and are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids and those derived from organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. Examples of organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts. The organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc. Chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds.

[0641] "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.

[0642] "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.

[0643] "Hydrate" refers to an association formed with a certain amount of water.

[0644] "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.

[0645] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with other chemical components, such as a pharmaceutically acceptable carrier, excipient, or diluent. The purpose of a pharmaceutical composition is to facilitate administration to an animal. Pharmaceutical compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity modifiers, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.

[0646] "Pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, ingredient, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or delivering a compound of the invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that is not unduly toxic or has adverse effects and is suitable for use in contact with animal tissue.

[0647] Some pharmaceutically acceptable carrier substances include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agarose; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Sterile pyrogen-free water; (17) Physiological saline; (18) Ringer's solution; (19) Alcohols, such as ethanol and propanol; (20) Phytophosphate buffer; (21) Other non-toxic substances compatible in pharmaceutical dosage forms, such as acetone.

[0648] Each pharmaceutically acceptable carrier should be compatible with the other components, for example, forming a formulation with the compound provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications to living tissues or organs, and with a reasonable benefit-risk ratio.

[0649] The pharmaceutical composition can be prepared into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The preparation methods and processes of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). DETAILED DESCRIPTION

[0650] The first group of preparation examples: Preparation of intermediates A1-A9

[0651] Intermediate A1. Preparation of 8-bromo-5-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-3-chloroisoquinoline

[0652] Step 1: Pd(PPh3)4 (8.2 g, 7.1 mmol) and bis-pinacol boronate (21.7 g, 85.6 mmol) were dissolved in toluene (50 mL). The atmosphere was purged with nitrogen, and but-3-yn-1-ol (5.0 g, 71.3 mmol) and acetic acid (3.6 mL, 62.8 mmol) were added. The reaction mixture was pre-stirred at room temperature for 5 minutes, then heated to 80°C and stirred for 0.5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-15%) to afford 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (a colorless oil, 12 g, 84.9%). MS (ESI) + )m / z=199.2[M+H] + .

[0653] 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 sequence, and stir at room temperature for 16 h. After the reaction was complete, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as an eluent 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] + .

[0654] 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, and heat to 60 ° C and stir for 5 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-10%) as the eluent 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] + .

[0655] 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 the hydrogen atmosphere, 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] + .

[0656] Intermediate A2. Preparation of 8-bromo-5-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-chloroisoquinoline

[0657] 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. 8-Bromo-5-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-chloroisoquinoline (Intermediate A2) was prepared according to the third and fourth steps of the synthesis of Intermediate A1. MS (ESI + )m / z=416.1[M+H] + .

[0658] Intermediate A3. Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine

[0659] Step 1: Under nitrogen, to a 40 mL single-necked flask were added 5-bromo-3-chloroisoquinoline (1.0 g, 4.1 mmol), N-[2-(tert-butyldimethylsilyloxy)ethyl]methanamine (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). The mixture was heated to 90°C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature and the reaction was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to give 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] + .

[0660] Step 2: Under nitrogen, 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-necked flask. Add N-iodosuccinimide (899.9 mg, 4.0 mmol) and heat to 60°C with stirring for 1 h. After the reaction is complete, cool to room temperature and quench the reaction with water (10 mL). The mixture is extracted with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-15%) as eluent to give 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] + .

[0661] Intermediate A4. Preparation of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloro-8-iodo-N-methylisoquinolin-5-amine

[0662] Step 1: In a 250 mL reaction flask, 3-(methylamino)propan-1-ol (5.0 g, 56.1 mmol) was dissolved in dichloromethane (100 mL). Imidazole (11.5 g, 168.3 mmol) was then added. The temperature was cooled to 0°C, and TBSCl (12.6 g, 84.2 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, water (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-30%) as the eluent to afford 3-(tert-butyldimethylsilyl)oxy)-N-methyl-1-propylamine (yellow oil, 5.5 g, 49%). MS (ESI) + )m / z=204[M+H] + .

[0663] 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.

[0664] Intermediate A5. Preparation of 8-bromo-3-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)isoquinoline

[0665] 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 flask. 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 mixture was extracted with ethyl acetate (40 mL × 3). 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 resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-8%) as eluent to give 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] + .

[0666] Intermediate A6. Preparation of 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-propanol

[0667] Step 1: In a 100 mL reaction flask, 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). p-Toluenesulfonic acid (11.23 g, 65.3 mmol) was then added. The mixture was heated to 60°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was isolated and purified by preparative liquid chromatography using water / acetonitrile (0-30%) as the eluent to afford 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] + .

[0668] Step 2: In a 100 mL reaction flask, 3-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (1.0 g, 3.3 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin (2.8 g, 6.7 mmol) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, saturated brine (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 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 isolated and purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as the eluent to obtain 3-(8-bromo-3-chloroisoquinolin-5-yl)propanal (yellow oil, 880 mg, 88%). MS (ESI) + )m / z=298.1[M+H] + .

[0669] Step 3: In a 100 mL reaction flask, 3-(8-bromo-3-chloroisoquinolin-5-yl)propanal (880 mg, 3.0 mmol) was dissolved in tetrahydrofuran (5 mL). L-proline (0.85 g, 7.4 mmol) and N-fluorobisbenzenesulfonamide (1.9 g, 5.9 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 h. After completion, the reaction was quenched with aqueous potassium bicarbonate (5 mL). The mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-60%) as the eluent to afford 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoropropanal (yellow solid, 360 mg, 36.6%). MS (ESI) +)m / z=334.0[M+H] + .

[0670] Step 4: In a 100 mL reaction flask, 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoropropanal (360 mg, 1.1 mmol) was dissolved in methanol (20 mL). The temperature was lowered to 0°C, and sodium borohydride (86.7 mg, 2.2 mmol) was slowly added. The reaction mixture was stirred at room temperature for 4 h. After the reaction was complete, water (30 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by preparative liquid chromatography using acetonitrile / 0.1% aqueous sodium bicarbonate (0-25%) as the eluent to afford 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] + .

[0671] Intermediate A7. Preparation of 3-(8-bromo-3-chloroisoquinolin-5-yl)-2,2-difluoro-1-butanol

[0672] Step 1: In a 100 mL reaction flask, 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). The temperature was cooled to 0°C, and TBAF (4.7 mL, 1 M solution in THF, 4.7 mmol) was added with stirring. After the addition was complete, 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 mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using 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%).

[0673] Step 2, Step 3, Step 4: Using 3-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol as the starting 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 synthesis of Intermediate A6. MS (ESI + )m / z=347.6[M+H] + .

[0674] Intermediate A8. Preparation of 4-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol

[0675] Step 1: Dissolve 3-chloroisoquinoline (100.0 g, 0.61 mol) in trifluoromethanesulfonic acid (2 L), cool to -10°C, and slowly add N-iodosuccinimide (151.3 g, 0.67 mol). Stir at -10°C for 1 hour. After the reaction is complete, slowly add ice water (10 L) to the reaction mixture, filter, collect the filter cake, and dissolve it in ethyl acetate (800 mL). Adjust the pH to 7 with aqueous ammonia. The resulting mixture is extracted with ethyl acetate (800 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-20%) to afford 3-chloro-5-iodoisoquinoline (pale yellow solid, 150 g, 84.7%). MS (ESI + )m / z=290.0[M+H] + .

[0676] 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 portions and stir at 0°C for 0.5 h. After the reaction is complete, slowly add ice water (4 L) to the reaction mixture, filter, collect the filter cake, dissolve it in ethyl acetate (5 L), dry it 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 a gradient elution of ethyl acetate / petroleum ether (0-20%) to obtain 8-bromo-3-chloro-5-iodoisoquinoline (pale yellow solid, 90 g, 47.4%). MS (ESI + )m / z=369.9[M+H] + .

[0677] 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 complete, the mixture was cooled to room temperature, water (40 mL) was added to the reaction solution, and the mixture 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 eluent gradient elution to give 4-(8-bromo-3-chloroisoquinolin-5-yl)butan-1-ol (white solid, 420 mg, 16.3%).

[0678] Intermediate A9. Preparation of 8-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-chloroisoquinoline

[0679] 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 starting 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 Step 3 of the synthesis of Intermediate A1. MS (ESI + )m / z=412.1[M+H] + .

[0680] Step 2: Under nitrogen, 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 on carbon (997.1 mg, 9.69 mmol) was added to displace the hydrogen atmosphere, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using a gradient elution of 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] + .

[0681] The second group of preparation examples: Preparation of intermediates B1-B11

[0682] Intermediate B1. Preparation of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0683] Step 1: Dissolve 2-chloropyrimidin-4-amine (20.0 g, 154.4 mmol) in tetrahydrofuran (200 mL), replace the nitrogen atmosphere, cool to 0°C, and sequentially add DMAP (1.9 g, 15.4 mmol), triethylamine (45.9 g, 453.9 mmol), and Boc2O (100.0 g, 458.5 mmol). Stir at room temperature for 16 h. After completion, quench the reaction with water (100 mL). Extract with ethyl acetate (100 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is separated by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-50%) to afford tert-butyl (tert-butyloxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (white solid, 50 g, 98.2%). MS (ESI) + )m / z=330.0[M+H] + .

[0684] 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-butoxycarbonyl)(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 complete, the mixture was cooled to room temperature and water (100 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was 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] + .

[0685] 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 complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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] + .

[0686] Intermediate B2. Preparation of 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)pyrimidin-4-amine

[0687] Step 1: Dissolve 3-bromo-2-methylpyridine (25.0 g, 145.33 mmol) in dichloromethane (200 mL) in a 500 mL single-necked flask at 0°C. Slowly add m-chloroperbenzoic acid (35.0 g, 202.83 mmol). Stir the reaction mixture at 30°C overnight. After the reaction is complete, slowly pour the reaction solution into ice water, adjust the pH to 10 with saturated sodium sulfite solution, and extract with ethyl acetate (1.2 L x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol / dichloromethane (0-10%) as the eluent to afford 3-bromo-2-methylpyridine 1-oxide (white solid, 25.0 g, 91.5%). MS (ESI) + )m / z=188.0[M+H] + .

[0688] 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-necked flask 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 mixture to room temperature and slowly pour into ice water to quench the reaction. Adjust the pH to 9 with saturated sodium carbonate solution, and extract with ethyl acetate (1.2 L x 3). The combined organic phases are washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to yield 3-bromo-2-methyl-4-nitropyridine 1-oxide (yellow solid, 15.2 g, 49.1%). MS (ESI) + )m / z=232.9[M+H] + .

[0689] Step 3: Dissolve 3-bromo-2-methyl-4-nitropyridine 1-oxide (15.2 g, 65.23 mmol) in acetonitrile (150 mL) in a 500 mL single-necked flask at room temperature. Slowly add phosphorus oxychloride (50.0 g, 326.11 mmol) dropwise, and heat to 80°C with stirring overnight. After the reaction is complete, cool the reaction mixture to 0°C, quench the reaction with water (100 mL), and extract with ethyl acetate (800 mL x 3). The combined organic phases are washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as the eluent to afford 3-bromo-4-chloro-2-methylpyridine 1-oxide (yellow solid, 11.6 g, 80.1%). MS (ESI) + )m / z=224.0[M+H] + .

[0690] Step 4: At room temperature, 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) were added to a 500 mL single-necked flask in sequence. The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The residue was washed with dichloromethane. The filtrate was diluted with water (100 mL) and extracted with dichloromethane (800 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as the eluent to afford 3-bromo-4-chloro-2-methylpyridine 4 (5.4 g, 50.6%) as a yellow oil. MS (ESI + )m / z=206.0[M+H] + .

[0691] Step 5: To a 250 mL single-necked flask at 0°C, add sodium hydride (1.2 g, 30.00 mmol, 60%) and N,N-dimethylformamide (80 mL) in sequence. Add 4-methoxybenzyl alcohol (4.0 g, 28.77 mmol) in portions, followed by 3-bromo-4-chloro-2-methylpyridine (5.4 g, 26.15 mmol). Heat to 80°C and stir for 2 h. After the reaction is complete, cool to room temperature and quench with water (50 mL). The mixture is extracted with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine (50 mL) and dried 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 give 3-bromo-4-((4-methoxybenzyl)oxy)-2-methylpyridine (white solid, 5.8 g, crude product). MS (ESI + )m / z=308.0[M+H] + .

[0692] Step 6: In a 250 mL single-necked flask, 3-bromo-4-((4-methoxybenzyl)oxy)-2-methylpyridine (5.8 g, 18.82 mmol) was dissolved in 1,4-dioxane (120 mL) at room temperature. Diboronic 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 sequentially. Under nitrogen, the mixture was heated to 100°C and stirred for 2 days. After the reaction was complete, the temperature was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as eluent to give 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] + .

[0693] Step 7: To a 250 mL single-necked flask 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), 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). Under nitrogen, heat to 100°C and stir overnight. After the reaction is complete, cool to room temperature, dilute with water (100 mL), and extract with ethyl acetate (500 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-20%) as eluent to give 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] + .

[0694] Intermediate B3. Preparation of 2-(4-methoxypyridin-3-yl)pyrimidin-4-amine

[0695] 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] + .

[0696] Intermediate B4. Preparation of 2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine

[0697] Step 1: In a 1000 mL three-necked round-bottom flask, 3-bromopyridin-4-ol (50 g, 289 mmol) was dissolved in acetonitrile (500 mL). Potassium carbonate (80 g, 581 mmol) was added, followed by the dropwise addition of benzyl bromide (54.4 g, 318 mmol). The reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography using methanol / dichloromethane (0-5%) as the eluent to yield 4-benzyloxy-3-bromopyridine (white solid, 60 g, 78.9%). MS (ESI) +)m / z=264.0[M+H] + .

[0698] Step 2: Under nitrogen, 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. Pd(dppf)Cl2 (3.11 g, 3.8 mmol), potassium acetate (11.2 g, 114.1 mmol), and bis-pinacol boronate (19.3 mg, 76.1 mmol) were added sequentially. The mixture was heated to 110°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction mixture was directly 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] + .

[0699] Step 3: Under nitrogen, in a 1000 mL three-necked round-bottom flask, (4-(benzyloxy)pyridin-3-yl)boronic acid (6.0 g, 26.2 mmol) was dissolved in a mixture of 1,4-dioxane and water (550 mL, 10 / 1, v / v). Tert-butyl (2-chloropyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (12.9 g, 39.3 mmol), Pd(dppf)Cl2 (2.1 g, 2.6 mmol), and potassium carbonate (10.9 g, 78.6 mmol) were added sequentially. The mixture was heated to 90°C and stirred for 1 h. After the reaction was complete, the temperature was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-5%) as eluent to give 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] + .

[0700] 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 mixture at room temperature for 1 h. After the reaction is complete, concentrate under reduced pressure to yield 2-(4-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine (brown solid, 4.0 g, crude product). MS (ESI) +)m / z=279.2[M+H] + .

[0701] Intermediate B5. Preparation of 2-(4-fluoropyridin-3-yl)pyrimidin-4-amine

[0702] Step 1: Under nitrogen, 3-bromo-4-fluoropyridine (1 g, 5.7 mmol) was dissolved in 1,4-dioxane (20 mL) in a 100 mL reaction flask. Bis-pinacol boronate (2.8 g, 11.0 mmol), Pd(dppf)Cl2 (415 mg, 0.57 mmol), and potassium acetate (1.7 g, 17.3 mmol) were added sequentially. The mixture was heated to 90°C and stirred for 5 h. After the reaction was complete, the temperature was cooled to room temperature and quenched by the addition of water (5 mL). The reaction was then concentrated under reduced pressure to afford 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (a black oil, 1 g, 78%). The crude product was used directly in the next step without further purification.

[0703] Step 2: Under nitrogen, in a 100 mL reaction flask, 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). 2-Chloropyrimidin-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 sequentially. The temperature was raised to 100°C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (100 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 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] + .

[0704] Intermediate B6. Preparation of 4-(4-aminopyrimidin-2-yl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0705] Step 1: In a 2000 mL round-bottom flask, dissolve 2,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (50.0 g, 446.4 mmol) in dichloromethane (1500 mL). Add potassium carbonate (308.0 g, 2232.1 mmol). Slowly add 2-(trimethylsilyl)ethoxymethyl chloride (111.2 g, 669.6 mmol) dropwise under ice-cooling. Stir at room temperature for 16 hours. After the reaction is complete, add water (500 mL), extract the mixture with dichloromethane (1000 mL x 3), and wash the combined organic phases with saturated brine (200 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-5%) as eluent to give 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] + .

[0706] Step 2: In a 100 mL round-bottom flask, 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). Cool to 0°C and add N-bromosuccinimide (43.9 g, 247.9 mmol) in portions. Stir at 25°C for 2 h. After the reaction is complete, quench the reaction with saturated sodium thiosulfate (1000 mL). The mixture is extracted with dichloromethane (500 mL x 3). The combined organic phases are washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (0-2%) as eluent to give 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] + .

[0707] 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-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate and tert-butyl (tert-butoxycarbonyl)(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 the synthesis of Intermediate B1. MS (ESI + )m / z=336.3[M+H] + .

[0708] Intermediate B7. Preparation of 2-(4-methoxypyridin-3-yl)-6-methylpyrimidin-4-amine

[0709] 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) sequentially, 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 resulting residue, and the mixture is extracted with ethyl acetate (200 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using 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] + .

[0710] Step 2 and Step 3: Using tert-butyl (tert-butoxycarbonyl)(2-chloro-6-methylpyrimidin-4-yl)carbamate 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 synthesis of Intermediate B4. MS (ESI + )m / z=217.2[M+H] + .

[0711] Intermediate B8. Preparation of 6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-amine trifluoroacetate

[0712] Step 1: Using 2,6-dichloropyrimidin-4-amine and Boc2O as raw materials, prepare tert-butyl (tert-butoxycarbonyl)(2,6-dichloropyrimidin-4-yl)carbamate (white solid) according to the method of the first step of the synthesis of intermediate B7. MS (ESI + )m / z=364.0[M+H] + .

[0713] Step 2: Under nitrogen protection, tert-butyl (tert-butoxycarbonyl)(2,6-dichloropyrimidin-4-yl)carbamate (50.0 g, 137.3 mmol) was dissolved in a 1,4-dioxane / water mixture (550 mL v / v, 10 / 1). 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) were added in sequence. The temperature was raised to 100 °C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (5000 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-20%) as an eluent by gradient elution to obtain tert-butyl (tert-butoxycarbonyl)(2-chloro-6-vinylpyrimidin-4-yl)carbamate (white oil, 27 g, 55.3%). MS (ESI + )m / z=356.1[M+H] + .

[0714] Step 3: Under nitrogen, dissolve tert-butyl (tert-butoxycarbonyl)(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) to displace the hydrogen atmosphere. Stir at room temperature for 4 h. After the reaction is complete, filter the reaction mixture through celite, wash the residue with ethyl acetate (200 mL), and concentrate the filtrate under reduced pressure to yield tert-butyl (tert-butoxycarbonyl)(2-chloro-6-ethylpyrimidin-4-yl)carbamate (black solid, 22.8 g, 98.6%). MS (ESI) + )m / z=358.2[M+H] + .

[0715] 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. The temperature was raised to 100 ° C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by 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] + .

[0716] Step 5: Using tert-butyl (tert-butoxycarbonyl)(6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-yl)carbamate (1.7 g, 3.95 mmol) as starting material, 6-ethyl-2-(4-methoxypyridin-3-yl)pyrimidin-4-amine trifluoroacetate (yellow solid, 1.2 g, 88.3%) was prepared according to the procedure of Step 4 of the synthesis of Intermediate B4. MS (ESI + )m / z=231.2[M+H] + .

[0717] 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

[0718] 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, and add cyclopropylmagnesium bromide (23.9 g, 164.7 mmol) dropwise. Stir at room temperature for 2 h. After the reaction is complete, cool to 0°C, add water (80 mL), filter, and wash the residue with ethyl acetate (100 mL). The filtrate is extracted with ethyl acetate (100 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using ethyl acetate / petroleum ether (5%) as the eluent to afford 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] + .

[0719] 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 starting 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 procedure for the second step of the synthesis of intermediate B1. MS (ESI + )m / z=462.2[M-100+H] + .

[0720] 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 was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using methanol / dichloromethane (1 / 10) as 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] + .

[0721] 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

[0722] 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 starting materials according to the second and third steps of Synthesis B1. MS (ESI) + )m / z=336.2[M+H] + .

[0723] Intermediate B11. Preparation of 2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-amine

[0724] 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). Tert-butyl tert-butoxycarbonyl)(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. The temperature was raised to 100 ° C and stirred for 1 h. After the reaction was complete, the temperature was lowered to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 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 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] + .

[0725] Step 2: In a 250 mL reaction flask, tert-butyl (tert-butoxycarbonyl)(2-(4-((4-methoxybenzyl)oxy)-2-methylpyridin-3-yl)-6-methylpyrimidin-4-yl)carbamate (200 mg, 0.37 mmol) was dissolved in methanol (5 mL). Sodium hydroxide solution (5 mL, 1.5 M) was added dropwise, and the mixture was heated to 80°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and extracted with dichloromethane (50 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 to give 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] + .

[0726] The third group of preparation examples: Preparation of intermediates C1-C8

[0727] Intermediate C1. Preparation of (2R,3S)-3-(methylsulfonylmethyl)-2-methylazetidine trifluoroacetate

[0728] Step 1: To a 40 mL single-necked flask, (2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-ol (5 g, 19.7 mmol) and dichloromethane (60 mL) were added sequentially. Triethylamine (6 g, 59.2 mmol) and methylsulfonyl chloride (3.39 g, 29.6 mmol) were then added at 0°C. The atmosphere was replaced with nitrogen and the mixture was stirred at room temperature for 12 h. The reaction was quenched by the addition of water (30 mL). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford (2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl methanesulfonate (5 g, 76.4%) as a pale yellow oil. MS (ESI) + )m / z=332.05[M+H] + .

[0729] Step 2: To a 250 mL single-necked flask, (2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl methanesulfonate (5 g, 15.09 mmol) and N,N-dimethylformamide (60 mL) were added sequentially. Sodium hydride (1.1 g, 45.3 mmol) was then added at 0°C. The atmosphere was replaced with nitrogen and the mixture was stirred at 0°C for 0.5 h. Methyl 2-methanesulfonylacetate (5.7 g, 37.7 mmol) was then added and the temperature was raised to 80°C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-46%) as the eluent by 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] + .

[0730] Step 3: To a 250 mL single-necked flask, methyl 2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-methylsulfonylacetate (4 g, 10.32 mmol) and N,N-dimethylformamide (40 mL) were added sequentially. Lithium chloride (3.5 g, 82.6 mmol) was added with stirring, and the mixture was heated to 150°C and stirred for 4 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-52%) to obtain (2R,3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (off-white solid, 2 g, 58.8%). MS (ESI) + )m / z=330.10[M+H] + .

[0731] Step 4: To a 50 mL single-necked flask, (2R,3S)-1-(diphenylmethyl)-3-(methylsulfonylmethyl)-2-methylazetidine (700 mg, 2.13 mmol), methanol (10.5 mL), and trifluoroacetic acid (0.35 mL) were added sequentially. Palladium hydroxide (208.9 mg, 1.49 mmol) was added while the mixture was allowed to stand. The hydrogen atmosphere was replaced and the mixture was stirred at room temperature for 12 h. The mixture was filtered and the filtrate was concentrated 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] + .

[0732] Preparation of Intermediate C2. N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0733] Step 1: Under nitrogen, dissolve (2R,3S)-3-amino-2-methylazetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.61 mmol) in dichloromethane (5 mL), then add triethylamine (489.0 mg, 4.83 mmol), cool to 0°C, slowly add methylsulfonyl chloride (184.5 mg, 1.61 mmol) dropwise with stirring, warm to room temperature and stir for 1 hour. After completion of the reaction, monitor by LCMS and concentrate under reduced pressure. The resulting residue is separated and purified by silica gel column chromatography using 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] + .

[0734] 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-necked bottle and stir at room temperature for 30 min. After the reaction is complete as monitored by LCMS, concentrate under reduced pressure at low temperature to obtain N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide (yellow oil, 400 mg, crude product). MS (ESI + )m / z=165.05[M+H] + .

[0735] Intermediate C3. Preparation of N-methyl-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0736] Step 1: Dissolve tert-butyl (2R,3S)-2-methyl-3-(methylsulfonamido)azetidine-1-carboxylate (450 mg, 1.7 mmol) in DMF (4.79 mL). Add sodium hydroxide (61.28 mg, 2.553 mmol) with stirring at 0°C to 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, and extract the mixed solution with ethyl acetate (50 mL×3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-50%) as the eluent in a gradient elution to obtain tert-butyl (2R,3S)-2-methyl-3-(N-methylmethanesulfonamido)azetidine-1-carboxylate (colorless transparent oil, 380 mg, 80.2%). MS (ESI + )m / z=179.1[M-100+H] + .

[0737] Step 2: Using (2R,3S)-2-methyl-3-(N-methylmethanesulfonyl)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] + .

[0738] Intermediate C4. Preparation of 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane

[0739] 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 flask. Then add triethylamine (1.5 g, 15.2 mmol) and 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 and quench with water (100 mL). The mixture is extracted with dichloromethane (150 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-60%) 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] + .

[0740] 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 completion of the reaction, concentrate under reduced pressure. The resulting residue is purified by high-pressure preparative liquid chromatography (column type: XBridge BEH Prep OBD Amide 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] + .

[0741] Intermediate C5. Dimethyl(((2R,3S)-2-methylazetidin-3-yl)imino)-λ 6 Preparation of -sulfoxide trifluoroacetate

[0742] Step 1: (2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl-methanesulfonate (10.0 g, 30.17 mmol) was dissolved in acetonitrile (100 mL), and Cs2CO3 (19.7 g, 60.34 mmol) and dimethylsulfonimide (4.2 g, 45.26 mmol) were added in sequence. The temperature was raised to 80°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature and water (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using 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] + .

[0743] Step 2: (((2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl)imino)dimethyl-λ 6 -sulfone (6.0 g, 18.27 mmol) was used as a raw material to prepare dimethyl (((2R, 3S)-2-methylazetidin-3-yl)imino)-λ 6 -sulfoxide trifluoroacetate (white solid, 5 g, 99.1%).

[0744] Preparation of Intermediate C6. N-methyl-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride

[0745] 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-methylmethylsulfonamido)pyrrolidine-1-carboxylate (yellow solid, 2 g, crude product) according to the method for synthesizing intermediate C4, step 1.

[0746] Step 2: Dissolve tert-butyl 3-(N-methylmethylsulfonamido)pyrrolidine-1-carboxylate (2.1 g, 7.54 mmol) in DCM (21 mL). Add a 4M solution of hydrochloric acid in 1,4-dioxane (11 mL, 45.26 mmol) and stir at room temperature for 2 h. After the reaction is complete, concentrate under reduced pressure to yield N-methyl-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride (yellow solid, 1.3 g, 88.8% yield over two steps).

[0747] Intermediate C7. Preparation of N-cyclopropyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0748] Step 1: Dissolve tert-butyl (2R,3S)-3-(cyclopropylamino)-2-methylazetidine-1-carboxylate (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 and add water (50 mL). The mixture is extracted with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield tert-butyl (2R,3S)-3-(cyclopropylamino)-2-methylazetidine-1-carboxylate as a white oil (500 mg, crude product).

[0749] 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 h. After the reaction is complete, cool to 0°C, add water (50 mL) to the reaction solution, and the mixture 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 to obtain (2R,3S)-3-(N-cyclopropylmethanesulfonamide)-2-methylazetidine-1-carboxylic acid tert-butyl ester (white oil, 350 mg, 52%).

[0750] 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 synthesizing intermediate C4.

[0751] Intermediate C8. Preparation of N-ethyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate

[0752] Step 1: Under nitrogen protection, dissolve tert-butyl (2R,3S)-2-methyl-3-(methylsulfonamido)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 sequence, and heat to 100 ° C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 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 and purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-50%) as the eluent to obtain tert-butyl (2R,3S)-3-(N-ethylmethylsulfonamido)-2-methylazetidine-1-carboxylate (white solid, 500 mg, 76.0%). MS (ESI + )m / z=293.3[M+H] + .

[0753] Step 2: Using (2R,3S)-3-(N-ethylmethylsulfonamido)-2-methylazetidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.71 mmol) as starting material, N-ethyl-N-((2R,3S)-2-methylazetidin-3-yl)methanesulfonamide trifluoroacetate (yellow oil, 320 mg, crude) was prepared according to the method of the second step of the synthesis of intermediate C4. MS (ESI + )m / z=193.2[M+H] + .

[0754] The fourth group of preparation examples: preparation of the final product

[0755] Example 1 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)-pyrazolocyclooctane-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 1 H-9-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazolocyclononane-4-(2,4-dimethylamino)-1-nitropropane 8 -yl)azetidin-3-yl)methanesulfonamide (final product 36), N-((2S,3R)-1-((S)-1 1 ,5-dimethyl-1 1H-8-Oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidine-1(4,5)-pyrazolocyclooctane-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)-pyrazolocyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide

[0756] Step 1: Dissolve intermediate A1 (1.5 g, 3.5 mmol), intermediate C3 (866.5 mg, 3.2 mmol), Xantphos Pd G4 (337.9 mg, 0.35 mmol) and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (15 mL), replace nitrogen, and heat to 100 ° C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-10%) as the eluent 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] + .

[0757] 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, and heated to 100 ° C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature and water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-10%) 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)-N-methylmethanesulfonamide (yellow solid, 100 mg, 64.9%). MS (ESI + )m / z=811.6[M+H] + The reaction conditions of this step can also be: Brettphos Pd G4, Cs2CO3 1,4-dioxane, 100°C.

[0758] 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-methylazetidin-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 complete, the mixture was cooled to room temperature and water (5 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-20%) as the eluent 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] + .

[0759] 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 the nitrogen atmosphere, add CMBP (42.6 mg, 0.18 mmol), and heat to 110 ° C and stir for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (5 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (5 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was 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)-pyrazolocyclooctane-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-(2,4-dimethylamino)-1-nitropropane 8 -yl)azetidin-3-yl)methanesulfonamide (final product 36).

[0760] 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).

[0761] 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).

[0762] Final product 1 was separated using a chiral preparative column (column type: CHIRALPAK IG 2*25 cm, 5 μm; mobile phase A: cyclohexane / dichloromethane (0.5% 2M NH3-MeOH) = 3:1, mobile phase B: EtOH; flow rate: 20 mL / min; wavelength: 220 / 254 nm) to obtain final product 2. The specific configuration of final product 2 is unknown.

[0763] Final product 2:

[0764] 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).

[0765] Preparation of final products 10, 12, 13, 78-79, 84, 110-111, 117, 119, 124, 139, 145, 148, 154-155, 166-167, 176, 187, and 190 of Examples 2-21

[0766] Using intermediates A1-A9, B1-B10, and C1-C8 as starting 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. These are shown in Table 1. The coupling conditions for the first step can also be: Pd2(dba)3, BINAP, tBuONa, toluene, 90-100°C or Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 100°C. The deprotection reaction conditions for the third step can also be: TBAF, TMEDA, THF, 70°C.

[0767] 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

[0768] Example 22 Preparation of Final Product 23 and Final Product 42

[0769] 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] + .

[0770] Step 2: To a 25 mL single-necked flask 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 in sequence. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. Ethanol (4 mL), tetrahydrofuran (12 mL), water (4 mL), and lithium hydroxide (357.1 mg, 14.91 mmol) were added in sequence at room temperature to the above residue, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, water (10 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (150 mL × 3) and dichloromethane (150 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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] + .

[0771] 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)-pyrimidin-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 preparative 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.

[0772] Final product 42:

[0773] 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).

[0774] 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)-pyrimidin-1(3,4)-pyridinecyclooctane (final product 84)

[0775] Final product 91 was prepared 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 the synthesis of the final product) and intermediate B11 as raw materials according to the above-mentioned synthesis method of final product 23.

[0776] MS (ESI + )m / z=545.2[M+H] + . 1H 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).

[0777] 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)-isoquinolin-2(2,4)-pyrimidin-1(3,4)-pyridylcyclooctane (final product 71)

[0778] 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] + .

[0779] 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 with stirring. 2mmol), heated to 70°C and stirred for 1h, cooled to room temperature, and concentrated under reduced pressure to obtain a crude product. The crude product 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] + .

[0780] 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 mixture 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 eluent to obtain 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%) as a white solid. MS (ESI + )m / z=549.3[M+H] + The reaction conditions for this step can also be: NaH (60%), ethanethiol, DMF, 120°C.

[0781] 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-((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 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)-isoquinolin-2(2,4)-pyrimidin-1(3,4)-pyridylcyclooctane (final product 71).

[0782] 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).

[0783] Preparation of final products 58 and 60 of Examples 25-26

[0784] The above-mentioned preparation method of the final product 71 was adopted, and the intermediates A1 or A9, intermediate B7, and intermediate C3 were used as raw materials to prepare the final products 58 and 60, as shown in Table 2.

[0785] Table 2 Characterization data of final products 58 and 60

[0786] 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 Preparation of -yl)azetidin-3-yl)methanesulfonamide (final product 20), final product 22

[0787] 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 mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 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 purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-50%) as the eluent to afford 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] + .

[0788] 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. The mixture was stirred at 60 ° C for 2 h. After the reaction was complete, the temperature was lowered to room temperature. The reaction solution was filtered through celite, and the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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, 320 mg, crude product). MS (ESI) + )m / z=678.4[M+H] + .

[0789] 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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-60%) as eluent to give 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] + .

[0790] 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 combined organic phases were 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)-pyrimidin-1(3,4)-pyridinecyclooctane-4 8The crude product was subjected to chiral separation (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: methyl tert-butylamine (0.5% 2M ammonia in methanol); mobile phase B: methanol / dichloromethane (1 / 1), flow rate: 20 mL / min; wavelength: 254 nm, 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)-isoquinolin-2(2,4)-pyrimidin-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.

[0791] Final product 22:

[0792] 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).

[0793] Example 28 Preparation of Final Product 38

[0794] Using intermediates A2, B4, and C3 as starting materials, final product 38 was prepared according to the synthesis method of final product 22. The specific configuration of final product 38 is unknown.

[0795] Final product 38:

[0796] 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).

[0797] Example 29 Preparation of Final Product 73

[0798] Using intermediates A1, B4, and C1 as starting materials, final product 71 was prepared according to the synthetic method for final product 22. Final product 71 was purified by high-pressure preparative liquid chromatography (XBridge Prep Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase: acetonitrile / water (0.1% formic acid); flow rate: 60 mL / min; gradient: 5%-35% over 7 min; wavelength: 254 nm) to afford final product 73. The specific configuration of final product 73 is unknown.

[0799] Final product 73:

[0800] 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).

[0801] 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)

[0802] 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 of Example 1) and intermediate B4 as raw materials, the final product 129 was prepared according to the first, second and fourth steps of the synthesis of the final product 20.

[0803] 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).

[0804] 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 -yl)azetidin-3-yl)methanesulfonamide (final product 25)

[0805] Step 1: Under nitrogen protection, 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) in a 40 mL reaction bottle. 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 cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 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 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] + .

[0806] 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, and 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 and water (50 mL) was added to quench the reaction. The mixed solution was extracted with dichloromethane (50 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography using 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%).

[0807] 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-methylazetidin-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 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 resulting 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] + .

[0808] Step 4: Under nitrogen, in a 40 mL reaction vial, 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). Ephos (10 mg, 0.019 mmol), Ephos Pd G4 (35 mg, 0.038 mmol), and cesium carbonate (184 mg, 0.57 mmol) were added sequentially. 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 quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting 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: XBridge Prep 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)-pyrimidin-1(3,4)-pyridinecyclooctane-4-yl)-1-[4-( ... 8 -yl)azetidin-3-yl)methanesulfonamide (10.2 mg, 9.8%).

[0809] 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).

[0810] 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)-pyrazolocyclooctane-4-nitropropane 8 Preparation of -yl)azetidin-3-yl)methanesulfonamide (final product 34)

[0811] Step 1 and step 2: Intermediate A5, intermediate C3, and intermediate B1 were used as raw materials, respectively, and 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 according to the method of Step 1 and Step 2 of Example 1. MS (ESI) + )m / z=767.4[M+H] + .

[0812] Step 3: In a 40 mL reaction bottle, 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) was dissolved in methanol (10 mL), and then p-toluenesulfonic acid (0.22 g, 1.30 mmol) was added. The temperature was raised to 60 ° C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature. 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] + .

[0813] 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 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)-pyrazolocyclooctane-4-nitropropane 8 -yl)azetidin-3-yl)methanesulfonamide.

[0814] 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).

[0815] 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)

[0816] 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 resulting 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] + .

[0817] 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 starting 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 for synthesizing the final product 20 in step 2. MS (ESI) + )m / z=634.3[M+H] + .

[0818] Step 3: Using N-((2R,3S)-1-(3-((2-(4-hydroxypyridin-3-yl)pyrimidin-4-yl)amino)isoquinolin-8-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide as starting 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 for synthesizing the final product 34 in Step 3. MS (ESI) + )m / z=550.1[M+H] + .

[0819] 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 raw material, N-((2R,3S)-1-(8-oxa-3-aza-4(3,5)-isoquinoline-2(2,4)-pyrimidin-1(3,4)-pyridinecyclooctane-4-yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide was prepared according to the method of Step 4 of Example 1. 8 -yl)-2-methylazetidin-3-yl)-N-methylmethanesulfonamide (final product 39).

[0820] 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).

[0821] 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)-pyrazolocyclooctane-4-nitropropane 8 Preparation of -yl)-2-methylazetidin-3-yl)methanesulfonamide (final product 137)

[0822] Step 1: Using 8-bromo-3-chloroisoquinoline (1.5 g, 6.19 mmol) and intermediate C2 (1.9 g, 6.80 mmol) as starting 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 for synthesizing the final product 1, Step 1. MS (ESI + )m / z=326.1[M+H] + .

[0823] 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), and the mixture is extracted with ethyl acetate (100 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is isolated and purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the 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] + .

[0824] 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 complete, the mixture was cooled to room temperature and water (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by 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-en-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 300 mg, 38.0%). MS (ESI + )m / z=396.1[M+H] + .

[0825] Step 4: Under nitrogen, N-((2R,3S)-1-(3-chloro-5-(4-hydroxy-1-en-2-yl)isoquinolin-8-yl)-2-methylazetidin-3-yl)methanesulfonamide (300.0 mg, 0.76 mmol) was dissolved in ethyl acetate (5 mL). Platinum dioxide (68.8 mg, 0.30 mmol) was added to displace the hydrogen atmosphere. The mixture was 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 yield 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] + .

[0826] 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, and the mixture 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 resulting 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)butan-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] + .

[0827] Step 6: Under nitrogen protection, N-((2R,3S)-1-(5-(4-((tert-butyldimethylsilyl)oxy)butan-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 complete, the mixture was cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting 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] + .

[0828] Step 7: 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) was dissolved in THF (1 mL), hydrochloric acid (2 M, 2 mL, 0.50 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was back-extracted with ethyl acetate (20 mL × 2). The aqueous phase was adjusted to pH 13 with NaOH solution, then extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 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 (yellow-green oil, 200 mg, crude product). MS (ESI) + )m / z=683.2[M+H] + .

[0829] 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) and add TFA (1 mL) dropwise. Stir at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was adjusted to pH 13 by adding NaOH (1 M) solution, stirred for 1 h, and concentrated under reduced pressure. The resulting 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] + .

[0830] 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 complete, H2SO4 solution (1M, 10 mL) was added to the reaction solution, and the mixture was back-extracted with ethyl acetate (10 mL×2). The aqueous phase was adjusted to pH 13 with NaOH solution (1 M), and then extracted with ethyl acetate (10 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by high-pressure preparative liquid chromatography 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)-pyrazolocyclooctane-4-nitropropane 8 -yl)-2-methylazetidin-3-yl)methanesulfonamide (yellow solid, 5 mg, 6.3%).

[0831] 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).

[0832] Preparation of final products 61, 77, 83, 86, 98, 123, 140, 157, 189, and 193 of Examples 35-42

[0833] Using the above-described method for preparing final product 137, intermediates B1-B10 and intermediates C1-C5 were used as starting materials to prepare final products 61, 77, 83, 86, 98, 123, 140, 157, 189, and 193, as shown in Table 3. Alternatively, the coupling reaction conditions for the first step could be: Xantphos Pd G3, Cs2CO3, dioxane, 100°C. Alternatively, the iodination reaction conditions for the second step could be: NIS, acetonitrile, acetic acid, rt. Alternatively, the TBS protecting group addition reaction conditions for the fifth step could be: imidazole, TBSCl, DMAP, DCM. Alternatively, the coupling reaction conditions for the sixth step could be: EPhos Pd G4, Ephos, Cs2CO3, 1,4-dioxane, 100°C. The deprotection reactions in steps 7 and 8 can be performed in a single step using TBAF, THF, and 70°C. If intermediates B3, B7, or B8 are used as starting materials, the demethylation reaction in step 8 can be performed using DMF, NaH, ethanethiol, DMF, and 120°C. Alternatively, the Mitsunobu reaction in step 9 can be performed using CMBP and toluene at 100-110°C.

[0834] Table 3 Characterization data of final products 61, 77, 83, 86, 98, 123, 140, 157, 189, 193

[0835] Preparation of comparative compound A

[0836] Comparative compound A was prepared according to the synthesis method of Example 1 using intermediate A1, intermediate C1 and intermediate B1 as raw materials 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).

[0837] Experimental example

[0838] 1. Cell proliferation inhibition experiment

[0839] CellTiter-Glo TM The live cell detection kit uses luciferase as a detector, and luciferase requires the participation of ATP in the luminescence process. Add CellTiter-Glo to the cell culture medium. TM The light signal is proportional to the amount of ATP in the system, which in turn is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to measure ATP content, cell proliferation can be monitored.

[0840] In this study, the celltiter-Glo (CTG) method was used to measure the proliferation inhibitory effect of the compounds prepared above 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 ).

[0841] 1. Experimental Design

[0842] Compounds were tested on selected cells and vehicle controls were set up for a total of 9 concentrations, with 2 replicates for each concentration.

[0843] 2. Reagents and Consumables

[0844] 3. Experimental Procedure

[0845] 3.1 Cell culture

[0846] a) All cells were cultured according to ATCC recommended methods. Cells were harvested during the logarithmic growth phase. Cell viability was measured to ensure that the cell viability was above 90%.

[0847] b) Cell culture medium: Add 90 μL of cell suspension to each well of a 96-well plate at the desired cell concentration.

[0848] c) Cell culture environment: culture at 37°C, 5% CO2, and 95% humidity.

[0849] 3.2 Drug dilution

[0850] a) Drug stock solution: The drug was dissolved in DMSO to prepare a 10 mM DMSO stock solution.

[0851] b) Drug Storage: DMSO stock solutions of drugs were stored in a desiccator at room temperature for short-term storage (up to 3 months). The remaining drugs were stored at -20°C for longer periods.

[0852] 3.3 Dosing

[0853] a) When testing the proliferation inhibitory 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 from 1 μM in a 10-point concentration gradient. When testing the proliferation inhibitory activity of the Ba / F3 EGFR wt wild-type cell line after the addition of EGF and the proliferation inhibitory activity of the A431 cell line, the drug was diluted 3-fold from 10 μM in a 10-point concentration gradient.

[0854] b) Prepare positive control drug and DMSO blank control.

[0855] c) Add 10 μL of 10x drug solution to each well of a 96-well plate seeded with cells, and set up two replicate wells for each drug concentration.

[0856] d) The cells in the drug-added 96-well plate were cultured at 37° C., 5% CO 2 , and 95% humidity for 72 hours before CTG analysis.

[0857] 3.4 Endpoint plate reading

[0858] a) Thaw CTG reagent, add 50 μL of CTG solution to each well, and shake well.

[0859] b) Mix on a shaker for 2 minutes and incubate at room temperature for 10 minutes.

[0860] c) Read the fluorescence value using a microplate reader.

[0861] 4. Data Processing

[0862] GraphPad Prism 8.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 value.

[0863] 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%.

[0864] 5. Experimental Results

[0865] 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)

[0866] Note: LRCS refers to L858R / C797S; LRCS refers to L858R / T790M / C797S; / : Not tested;

[0867] 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 IC 50 As shown in Table 4.

[0868] As can be seen in Table 4, the compounds of the present invention exhibited good antiproliferative activity against Ba / F3 (EGFR-L858R / C797S), Ba / F3 (EGFR-L858R / T790M / C797S), NCI-H1975, and PC9 cell lines, but exhibited weaker antiproliferative activity against Ba / F3 EGFR wt+EGF and A431 cell lines expressing wild-type EGFR, demonstrating that the compounds of the present invention possess good inhibitory activity and selectivity against cell lines expressing EGFR mutations. The data in Table 4 demonstrate that selectivity is enhanced when the L2 groups of the isoquinoline and pyrazole linkers of the compounds of the present invention have substituents (e.g., compounds 111, 119, 187, 190) or when the pyrazole 3-position has a substituent (e.g., compound 117).

[0869] 2. Cassette pharmacokinetic testing of compounds in mice

[0870] Objective: To investigate the pharmacokinetic behavior of the compounds of the present invention in mice by LC / MS / MS after oral gavage (PO) of the compounds using ICR mice as test subjects and to evaluate their pharmacokinetic characteristics by detecting the drug concentrations in plasma at different time points.

[0871] Drug Preparation: The compounds were prepared into clear solutions in 10% NMP + 10% Solutol + 80% Saline as the solvent for PO administration via cassette dosing. The compounds were administered at doses of 10 mg / kg, 15 mg / kg, or 20 mg / kg. Pharmacokinetic parameters are shown in Table 5.

[0872] Table 5 Pharmacokinetic test results of cassette in mice

[0873] As can be seen from Table 5, the compounds of the present invention have good exposure.

[0874] 3. P-gp substrate evaluation experiment

[0875] 1. Experimental Design

[0876] 1.1 Cell culture

[0877] 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.

[0878] 2) MDCKII-MDR1 cells were cultured in T-75 cell culture flasks in an incubator set at 37°C, 5% CO2, and 95% relative humidity. Cells were seeded in Transwell plates when they reached 70-90% confluence.

[0879] 3) Before seeding cells, add 50 μL of cell culture medium to each well of the upper Transwell chamber and 25 mL of cell culture medium to the lower culture plate. Incubate the culture plate in a 37°C, 5% CO2 incubator for 1 hour before seeding cells.

[0880] 4) Gently wash the cells with 5 mL of PBS. Discard the PBS and add 1.5 mL of trypsin containing EDTA. Incubate at 37°C for 5 to 10 minutes until the cells are completely detached. Add serum-containing medium to terminate the digestion.

[0881] 5) Transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120 × g for 10 minutes.

[0882] 6) Resuspend the cells in culture medium to a final concentration of 1.56 × 10 6 cells / mL.

[0883] 1.2 MDCKII-MDR1 cell inoculation

[0884] 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 × 10 5 cells / cm 2 .

[0885] 2) Start changing the medium 24 hours after inoculation and culture for 4-8 days, changing the medium every other day.

[0886] 1.3 Evaluation of cell monolayer integrity

[0887] 1) After 4-8 days of culture, MDCKII-MDR1 and MDCKII should be fully confluent and differentiated. At this point, they can be used for penetration assays.

[0888] 2) The resistance of the monolayer membrane was measured using a resistance meter (Millipore, USA), and the resistance of each pore was recorded.

[0889] 3) After the assay is completed, place the Transwell culture plate back into the incubator.

[0890] 4) Calculation of resistance value:

[0891] Measure the resistance value (ohms) x film area (cm 2 )=TEER value (ohm·cm 2 )

[0892] If the TEER value is less than 42 ohms·cm 2 , then the hole cannot be used for penetration test.

[0893] 1.4 Drug penetration test

[0894] 1) Remove the MDCKII-MDR1 Transwell plate from the incubator. Rinse the cell monolayer twice with HBSS (10 mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes.

[0895] 2) Determine the transport rate of the compound from the apical to the basolateral side. Add 125 μL of test drug or control drug in HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical) and 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the lower chamber (basolateral).

[0896] 3) Determine the transport rate of the compound from the basolateral to the apical side. Add 285 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the upper chamber (apical side), and add 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer containing the test drug or control drug to each well of the lower chamber (basolateral side).

[0897] 4) Combine the upper and lower transfer devices and incubate at 37°C for 2 hours.

[0898] 5) After incubation, sample 50 μL from each well of the upper and lower chambers of the Transwell plate and transfer to new sample tubes. Add 4 volumes of acetonitrile containing internal standards (200 nM alprazolam, 200 nM labetalol, 200 nM diclofenac, 100 nM tolbutamide) to each tube. Vortex for 5 minutes and centrifuge at 3,220 g for 15 minutes. Aspirate 100 μL of the supernatant, dilute with an equal volume of water, and perform LC-MS / MS analysis. All samples were prepared in triplicate.

[0899] 6) After 2 hours of incubation, the integrity of the cell monolayer membrane was assessed by fluorescein leakage. The fluorescein stock solution was diluted to a final concentration of 100 μM in HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescein solution was added to each well of the upper Transwell insert, and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from each well and transferred to a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0900] 2. Data Processing

[0901] The data were calculated using Excel. The apparent permeability coefficient (P app , unit: cm / s) is calculated using the following formula:

[0902] The membrane area in the formula is the Transwell-96 well plate membrane area (0.143 cm 2 ); the incubation time unit is seconds (s).

[0903] The efflux rate is calculated using the following formula:

[0904] Table 6. Efflux rates of the tested compounds

[0905] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications may be made to the present invention, and such improvements and modifications also fall within the scope of protection of the present invention.

Claims

1. An amino heteroaryl macrocyclic compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof: Among them, In formula I, Ring A is a 5- to 12-membered heteroaryl, 6- to 12-membered aryl or 3- to 12-membered heterocyclic group, and the 5- to 12-membered heteroaryl, 6- to 12-membered aryl or 3- to 12-membered heterocyclic group is connected to NH and Ring M through two different atoms respectively; Ring E is a 5- to 12-membered heteroaryl, 6- to 12-membered aryl or 3- to 12-membered heterocyclic group, and the 5- to 12-membered heteroaryl, 6- to 12-membered aryl or 3- to 12-membered heterocyclic group is connected to NH and X1 through two different atoms respectively; Ring M is a 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 3- to 12-membered heterocyclic group, 3- to 12-membered cycloalkyl or 3- to 12-membered cycloalkenyl, and the 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 3- to 12-membered heterocyclic group, 3- to 12-membered cycloalkyl or 3- to 12-membered cycloalkenyl is connected to Ring A and X2 through two different atoms; L2 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, containing 1 - 3 C's selected from N, O, S, C(=O), S(=O)(=W 1 ) 1- 6 - heteroalkylene, containing 1 - 3 C's selected from N, O, S, C(=O), S(=O)(=W 1 ) 2-6 heteroalkenylene, said C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, containing 1 - 3 C's selected from N, O, S, C(=O), S(=O)(=W 1 ) 1-6 heteroalkylene, containing 1 - 3 C's selected from N, O, S, C(=O), S(=O)(=W 1 ) 2-6 heteroalkenylene is optionally substituted by one or more identical or different R 5 substituents; X1 and X2 are each independently absent or each independently is NR 1a , -C(R 2a )(R 3a )-, O, S, C(=O) or S(=O)(=W 1 ); R 1 Each independently is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2- 6-enyl, C 2-6 alkynyl, a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-6 enyl, C 2-6 alkynyl, a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl is optionally substituted by one or more R′; R 2 and R 3 are each 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), wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 0-6 Alkyl-3- to 12-membered cycloalkyl, C 0-6 Alkyl-3- to 12-membered heterocyclic group, C 0-6 Alkyl-6- to 10-membered aryl, C 0-6 Alkyl-5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl-C 1-6 Alkyl, 3- to 12-membered heterocyclic group-C 1-6 Alkyl, 6- to 10-membered aryl-C 1- 6-Alkyl, 5- to 10-membered heteroaryl-C 1-6 The alkyl is optionally substituted by one or more R′; or two Rs 2 together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclic, 5- to 14-membered heteroaryl or 6- to 14-membered aryl group, which 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocyclic, 5- to 14-membered heteroaryl or 6- to 14-membered aryl group is optionally substituted by one or more R′s; R 4 is R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4- to 14-membered heterocyclic group, (R 30 ) p N-Y(R 20 ) p -C 0-4 alkyl-4- to 14-membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-5- to 6-membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4- to 12-membered cycloalkyl, wherein said R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4- to 14-membered heterocyclic group, (R 30 ) p N-Y(R 20 ) p -C 0-4 alkyl-4- to 14-membered heterocyclic group, R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-5- to 6-membered heteroaryl or R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4- to 12-membered cycloalkyl optionally substituted with one or more R′; Alternatively, R 4 is R 5 Each independently 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- to 12-membered cycloalkyl, C 0-6 alkyl-3- to 12-membered heterocyclic group, C 0-6 alkyl-6- to 10-membered aryl, C 0-6 alkyl-5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl-C 1-6 alkyl, 3- to 12-membered heterocyclic group-C 1-6 alkyl, 6- to 10-membered aryl-C 1-6 alkyl, 5- to 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 , NR e2 , NR e1 , NR 1 )R e2 , NR e1 , NR e2 , NR e1 , 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), wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkyl-3- to 12-membered cycloalkyl, C 0-6 alkyl-3- to 12-membered heterocycloalkyl, C 0-6 alkyl-6- to 10-membered aryl, C 0-6 alkyl-5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl-C 1-6 alkyl, 3- to 12-membered heterocycloalkyl-C 1-6 alkyl, 6- to 10-membered aryl-C 1-6 alkyl, 5- to 10-membered heteroaryl-C 1- 6 The alkyl is optionally substituted by one or more R′; or two Rs 5 together with their respective attached atoms form a 3- to 12-membered cycloalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, 3- to 12-membered cycloalkenyl or 3- to 12-membered heterocyclic group, which 3- to 12-membered cycloalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, 3- to 12-membered cycloalkenyl or 3- to 12-membered heterocyclic group is optionally substituted by one or more R′s; R 1a and R 2a each independently do not exist or each independently is a hydrogen atom, a deuterium atom, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, 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 , wherein the C 1-6 alkyl group, the halogenated C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclic group, the 6- to 10-membered aryl group, the 5- to 10-membered heteroaryl group is optionally substituted by one or more R'; or R 2 and R 1a together with the atoms to which they are attached form a 3- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, which 3- to 12-membered heterocyclic group or 5- to 12-membered heteroaryl group is optionally substituted with one or more R' groups; or R 3 and R 1a together with the atoms to which they are attached form a 3- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, which 3- to 12-membered heterocyclic group or 5- to 12-membered heteroaryl group is optionally substituted by one or more R' groups; R 3a is a hydrogen atom, deuterium atom, halogen, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 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 , NR 1 S(=O)(=W 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), wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by one or more R′; or R 2a and R 3a together with the attached C atom form a 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclic group, which 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclic group is optionally substituted by one or more R' or R 2 and R 3a together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 12-membered aryl or 5- to 12-membered heteroaryl group, which 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 12-membered aryl or 5- to 12-membered heteroaryl group is optionally substituted by one or more R′; or R 3 and R 3a together with the atoms to which they are attached form a 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 12-membered aryl or 5- to 12-membered heteroaryl, which 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 12-membered aryl or 5- to 12-membered heteroaryl is optionally substituted by one or more R′; R′ is a deuterium atom, halogen, CN, NO2, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 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 each independently is a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group is optionally substituted by one or more R″; or R e1 and R e2 forms, together with the atom to which it is attached, a 3- to 12-membered heterocyclic group, which 3- to 12-membered heterocyclic group is optionally substituted with one or more of the following groups: deuterium atom, halogen, CN, NO2, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, OR g1 ; or R f1 and R f2 forms a 3- to 12-membered heterocyclic group together with the atom to which it is attached, said 3- to 12-membered heterocyclic group being optionally substituted with one or more of the following groups: a deuterium atom, a halogen, CN, NO2, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, OR g1 ; R″ is a deuterium atom, halogen, CN, NO2, C 1-6 alkyl, halo-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 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 each independently is a hydrogen atom, a deuterium atom, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl or a 3- to 12-membered cycloalkyl; W 1 is none, O or NR g1 ; Y is N or C; represents a single bond or a double bond; R 30 is a hydrogen atom, a deuterium atom, C 1-6 alkyl, halo 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- to 12-membered cycloalkyl or C 0-6 alkyl-3- to 12-membered heterocyclic group, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkyl-3- to 12-membered cycloalkyl and C 0-6 alkyl-3- to 12-membered heterocyclic group is optionally substituted by one or more R'; or, two R 30 together with the atoms to which they are respectively attached form a 3- to 6-membered cycloalkyl or a 3- to 7-membered heterocyclic group, and the 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted by one or more R'; R 20 、R 40 、R 50 、R 60 each independently is a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, C 1-6 alkyl, halo-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- to 12-membered cycloalkyl, C 0-6 alkyl-3- to 12-membered heterocyclic group or oxo(=O), wherein the C 1-6 alkyl, halo-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- to 12-membered cycloalkyl and C 0-6 alkyl-3- to 12-membered heterocyclic group are optionally substituted by one or more R'; or, two R 20 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 7-membered heterocyclic group, and the 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted by one or more R'; Alternatively, R 20 and R 50 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group, which 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted by one or more R'; Alternatively, R 40 and R 60 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group, which 3- to 6-membered cycloalkyl or 3- to 7-membered heterocyclic group is optionally substituted by one or more R′; m, n, and t are each independently 0, 1, 2, 3, or 4; p is each independently 1 or 2.

2. The amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to claim 1, wherein, In formula I, Ring A is a 5- to 6-membered heteroaryl; Preferably, Ring A is pyridine, pyrimidine, pyridazine, pyrazine, triazine or thiazole; More preferably, ring A is selected from the following groups: * a Indicates the connection site with NH, * b Table indicates the connection site to Ring M; Most preferably, ring A is selected from the following groups: * a Indicates the connection site with the N atom of NH, * b Indicates the connection site with the M ring; Further optionally, in formula I, Ring E is a 9- to 10-membered heteroaryl, and the 9- to 10-membered heteroaryl is connected to NH and X1 through two different atoms respectively; Preferably, the E-ring is More preferably, ring E is Most preferably, ring E is selected from Wherein, --- or -- represents none or a single bond; U 1 Absent or N, CH or C; U 2 Absent or N, CH or C; U 3 is N, C, NR 100 , O, S or C(=O); U 4 and U 5 are each independently N or C, and U 4 and U 5 are not both N at the same time; U 6 is 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 each independently represents a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 0-6 alkyl-3- to 12-membered cycloalkyl group or a C 0-6 alkyl-3- to 12-membered heterocyclic group; When U 1 is absent, U 2 and U 7 are connected by a single bond or a double bond; when U 2 is absent, U 1 and U 3 are connected by a single bond or a double bond; When U 1 and U 2 are N or CH, at most three of U 1 , U 2 , U 3 , U 4 , U 5 and U 7 are N simultaneously.

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

4. The amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 3, wherein, In formula I, L2 is C 1-6 alkylene, C 1-6 alkenylene or a C 1 heteroalkylene containing 1-3 C's selected from N, O, S, C(=O), S(=O)(=W 1-6 ), wherein the C 1-6 alkylene, C 1-6 alkenylene or a C 1 heteroalkylene containing 1-3 C's selected from N, O, S, C(=O), S(=O)(=W 1-6 ) is optionally substituted by one or more identical or different R 5 substituents; Preferably, L2 is methylene, ethylene, propylene, butylene, pentylene, vinylidene, propenylene, butenylene or ethoxy, and the methylene, ethylene, propylene, butylene, pentylene, vinylidene, propenylene, butenylene or ethoxy is optionally substituted by one or more identical or different R 5 substituted; Wherein, R 5 is 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, and 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 by one or more R'; Alternatively, two Rs 5 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl, phenyl, 4- to 7-membered heterocyclic, 5- to 6-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted by one or more R's; 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 cyclopropoxy group or an oxo group; Alternatively, two Rs 5 together with the atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine, which cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine or piperidine is optionally substituted by one or more R's; 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; Alternatively, two Rs 5 together with their respective attached atoms form cyclopropyl, cyclobutyl, cyclopentyl or oxetane, which cyclopropyl, cyclobutyl, cyclopentyl or oxetane is optionally substituted with one or more deuterium atoms, halogens, methyl, ethyl, cyclopropyl; More preferably, L2 is Among them, R 5a 、R 5b 、R 5c 、R 5a′ 、R 5b′ 、R 5c′ are each independently R 5 ; preferably, R 5a 、R 5b 、R 5c 、R 5a′ 、R 5b′ 、R 5c′ are each 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, and 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 alkoxy is optionally substituted by one or more hydroxyl groups, amino groups, cyano groups, halogens, C 1-4 alkyl, 3-6 membered cycloalkyl or oxo; Alternatively, R 5a and R 5a′ together with the attached atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted with one or more R'; Alternatively, R 5b and R 5b′ together with the linked atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted with one or more R'; Alternatively, R 5c and R 5c′ together with the attached atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted by one or more R'; Alternatively, R 5a and R 5b together with the attached atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted with one or more R'; Alternatively, R 5a and R 5c together with the attached atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted by one or more R'; Alternatively, R 5b and R 5c together with the attached atom form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic or 3- to 6-membered cycloalkenyl group, which is optionally substituted with one or more R'; More preferably, R 5a , R 5b , R 5c , R 5a′ , R 5b′ , R 5c′ are each independently a hydrogen atom, a deuterium atom, F, Cl, Br, 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 cyclopropoxy group or an oxo group; Alternatively, R 5a and R 5a′ together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted with one or more R'; Alternatively, R 5b and R 5b′ together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted by one or more R'; Alternatively, R 5c and R 5c′ together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted by one or more R'; Alternatively, R 5a and R 5b together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted with one or more R'; Alternatively, R 5a and R 5c together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted by one or more R'; Alternatively, R 5b and R 5c together with the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, pyran, azetidine, piperidine or morpholine, which are optionally substituted by one or more R'; Wherein, 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, cyclopropoxy or oxo.

5. An amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 4, wherein, In formula I, R 1 is independently selected from a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2- 4-enyl, C 2-4 alkynyl, a 3- to 6-membered cycloalkyl or oxo, and the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-4 enyl, C 2-4 alkynyl, a 3- to 6-membered cycloalkyl is optionally substituted by one or more R'; Preferably, R 1 is independently 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 cyclopropoxy group or an oxo group; Preferably, R 2 is independently selected from a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 alkyl, halo 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), wherein the C 1-6 alkyl, halo 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 heterocyclic group-C 1-6 alkyl is optionally substituted by one or more deuterium atoms, halogens, hydroxyl groups, methyl groups, ethyl groups, methoxy groups, ethoxy groups or cyclopropyl groups; Preferably, R 2 is independently a hydrogen atom, a deuterium atom, a halogen, CN, methyl, ethyl, isopropyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino, and the methyl, ethyl, isopropyl, vinyl, ethynyl, difluoromethyl, methoxy, ethoxy, isopropoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino is optionally substituted by one or more deuterium atoms, halogens, hydroxyl groups, methoxy groups, ethoxy groups or cyclopropyl groups; Preferably, R 3 is independently selected from a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 alkyl, halo-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 , and the C 1-6 alkyl, halo-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 is optionally substituted by one or more deuterium atoms, F, Cl, hydroxyl, methyl, ethyl, methoxy, ethoxy or cyclopropyl; Preferably, R 3 is 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 cyclopropoxy group, an oxo group, C(=O)R e1 , C(=O)NR e1 or S(=O)2R e1 ; wherein, 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 is independently a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group or a cyclopropyl group; More preferably, R 2 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, and the methyl group, ethyl group or methoxy group is optionally substituted with one or more halogens; More preferably, R 3 is a hydrogen atom, a deuterium atom, a halogen, a methyl group, an ethyl group, a cyclopropyl group, a dimethylamino group, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)2-cyclopropyl.

6. The amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 5, 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; Wherein, R 1a and R 2a are each independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or a 3- to 12-membered cycloalkyl group, and the C 1-6 alkyl group, the halogenated C 1-6 alkyl group or the 3- to 12-membered cycloalkyl group is optionally substituted by one or more R'; R 3a is a hydrogen atom, a deuterium atom, a halogen, CN, C 1-6 alkyl, a hydroxyl group, hydroxy C 1-6 alkyl, C 1-6 alkoxy, an amino group, C 1-6 alkylamino or di(C 1-6 alkyl)amino, said C 1-6 alkyl, hydroxy 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 are each independently a hydrogen atom, a deuterium atom, F, Cl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or hydroxyethyl; or R 3 and R 1a together with the attached atom form 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; Alternatively, R 2a and R 3a together with the connected C atom form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group, which is optionally substituted by one or more R'; Alternatively, R 2a and R 3a together with the connected C atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl or oxetanyl, which are optionally substituted by one or more R'; Alternatively, R 2a and R 3a together with the connected C atom form cyclopropyl, cyclobutyl, oxiranyl or oxetanyl, which are optionally substituted by one or more halogen, methyl or hydroxy groups.

7. The amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 6, wherein, In formula I, R 4 is R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4-7-membered heterocyclic group, (R 30 ) p N-Y(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 the R 30 -S(=O)(W 1 )-Y(R 20 ) p -C 0-4 alkyl-4-7-membered heterocyclic group, (R 30 ) p N-Y(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 optionally substituted by one or more R'; or, R 4 is Preferably, R 4 is selected from More preferably, R 4 is Most preferably, R 4 is selected from wherein, W 1 is none, O or NH; Y is N or C; Y 1 Absent or N or C; Y 2 and Y 3 are each independently NR 70 , N, CR 70 , O or S; R 70 Each independently is a hydrogen atom, a deuterium atom, an amino group, C 1-6 alkyl, halo C 1-6 alkyl, C 0-2 alkyl-3- to 12-membered cycloalkyl or C 0- 2-alkyl-3- to 12-membered heterocyclic group, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 0-2 alkyl-3- to 12-membered cycloalkyl or C 0-2 alkyl-3- to 12-membered heterocyclic group is optionally substituted with one or more deuterium atoms, CN, hydroxy or halogen; q1 or q2 is each independently 1, 2 or 3; Further optionally, R 30 is independently a hydrogen atom, a deuterium atom, an amino group, C 1-6 alkyl, halo C 1-6 alkyl, C 0-2 alkyl-3-12-membered cycloalkyl or C 0-2 alkyl-3-12-membered heterocyclic group, and the C 1-6 alkyl, halo C 1-6 alkyl, C 0-2 alkyl-3-12-membered cycloalkyl or C 0-2 alkyl-3-12-membered heterocyclic group is optionally substituted by one or more deuterium atoms, CN, hydroxyl groups or halogens; Preferably, R 30 is independently 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, and the amino group, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoromethyl group, difluoroethyl group, trifluoroethyl group or hydroxyethyl group is optionally substituted by one or more halogen or deuterium atoms; Alternatively, two Rs 30 together with the attached atom form azetidinyl, pyrrolidinyl, piperidinyl, which are optionally substituted by one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen; Preferably, R 20 , R 40 , R 50 , R 60 are each independently a hydrogen atom, a deuterium atom, a halogen, CN, an amino group, a hydroxyl group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a C 0-2 alkyl-3-12-membered cycloalkyl group or a C 0-2 alkyl-3-12-membered heterocyclic group or oxo(=O), and the C 1-6 alkyl group, the halogenated C 1-6 alkyl group, the C 1-6 alkoxy group, the C 1-6 alkylamino group, the di(C 1-6 alkyl)amino group, the C 0-2 alkyl-3-12-membered cycloalkyl group or the C 0-2 alkyl-3-12-membered heterocyclic group is optionally substituted by one or more deuterium atoms, hydroxyl groups, C 1-3 alkyl groups or halogens; Preferably, R 20 , R 40 , R 50 , R 60 are each 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 cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group, a hydroxyethyl group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a methoxy group, an ethoxy group or an oxo group, and the amino group, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoroethyl group, trifluoroethyl group, hydroxyethyl group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, methoxy group or ethoxy group is optionally substituted by one or more halogen atoms, methyl groups or deuterium atoms; Alternatively, two Rs 20 together with the atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen; Alternatively, R 20 and R 50 together with the atoms to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, cyclobutyl, cyclopentyl or cyclohexyl, which azetidinyl, pyrrolidinyl, piperidinyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano; Alternatively, R 40 and R 60 together with the atoms to which they are attached form azetidinyl, pyrrolidinyl, cyclohexyl, said azetidinyl, pyrrolidinyl, cyclohexyl being optionally substituted by one or more methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, halogen, cyano; More preferably, R 30 is independently a hydrogen atom, an amino group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a difluoroethyl group, a trifluoroethyl group or a hydroxyethyl group; More preferably, R 20 , R 40 , R 50 , R 60 is each 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 amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 7, wherein, The compound is selected from the structural formulas shown in Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII Among them, 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 are defined as described in any one of claims 1-9; Among them, 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 are defined as described in any one of claims 1-9; Among them, 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 are defined as described in any one of claims 1-9; U 8 is N, Cr 1 , O, S or C(=O); U 9 Absent or N, CR 1 , O, S or C(=O); U 11 is N, Cr 1 , O, S or C(=O); Among them, 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 are defined as described in any one of claims 1-9; U 9 is absent 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 is -N(R 3a ′)-, -C(R 3a ′)=C(R 3a ′)-; q is 1, 2 or 3; R 1 ′ is a hydrogen atom, a deuterium atom, a halogen, CN, NO2, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6-alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 6-alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 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, a hydroxyl group, hydroxyethyl, an amino group, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, vinyl, ethynyl, trideuteriomethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy or oxo; Wherein, in Formula IV, Formula V, Formula VI or Formula VII, 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- to 12-membered cycloalkyl, C 0-6 alkyl-3- to 12-membered heterocyclic group, OR e1 , and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkyl-3- to 12-membered cycloalkyl, C 0-6 alkyl-3- to 12-membered heterocyclic group 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 trimethylsilyl 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 oxiranyl group, an oxetanyl group, an aziridinyl group, an azetidinyl group, and the methyl group, ethyl group, propyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, oxiranyl group, oxetanyl group, aziridinyl group, azetidinyl group are optionally substituted by one or more of the following groups: deuterium atom, fluorine, chlorine, bromine, CN, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, oxo; Preferably, 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, and 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 is optionally substituted by one or more R′; Preferably, R 3b ′ is a hydrogen atom, a deuterium atom, fluorine, chlorine, bromine, CN, NO2, methyl, ethyl, propyl, trideuteriomethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, and the methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl are optionally substituted with one or more of the following groups: deuterium atom, fluorine, chlorine, bromine, CN, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxo.

9. An amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule or solvate thereof according to any one of claims 1 to 8, wherein, The compound represented by any one of Formulas I to VII is selected from the following compounds:

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

11. Use of the aminoheteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled compound, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof according to any one of claims 1 to 9 and / or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating diseases mediated by abnormal EGFR; Preferably, the disease is a neoplastic disease; More preferably, the neoplastic 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, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

12. A method for treating a disease mediated by abnormal EGFR, the method comprising administering to a patient in need thereof the amino heteroaryl macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope-labeled substance, deuterated substance, N-oxide, prodrug molecule, hydrate or solvate thereof as described in any one of claims 1 to 9 and / or the pharmaceutical composition as described in claim 10; Preferably, the patient is preferably a mammal, and the mammal is preferably a human; Preferably, the disease is a neoplastic disease; More preferably, the neoplastic 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, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

Images