Heteroaryl macrocyclic compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a heteroaryl macrocyclic compound, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a therapeutic agent, wherein the structure of the heteroaryl macrocyclic compound is as shown in formula I: formula I, wherein the definitions of A, E, M, L1, L2, X1, X2, and X3 are as stated in the description. The heteroaryl macrocyclic compound has a good inhibitory effect on an epidermal growth factor receptor (EGFR), and can be used for the treatment of related diseases induced by EGFR abnormalities, especially in the treatment of cancer.

Description

Heteroaryl macrocyclic compounds, their preparation methods and applications Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to heteroaryl macrocyclic compounds and pharmaceutical compositions thereof, and also to the use of such compounds and pharmaceutical compositions thereof in the treatment of protein kinase-mediated diseases, particularly as EGFR inhibitors and in the preparation of medicaments for the prevention and / or treatment of EGFR-mediated diseases (such as cancer). Background Technology

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

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

[0004] EGFR is an oncogene, leading to targeted therapies using small molecule inhibitors. In non-small cell lung cancer (NSCLC), 50%-80% of patients have EGFR mutations (primarily the exon 19 deletion mutation Ex19Del and the L858R mutation, where lysine is replaced by arginine at position 858 in exon 21; both are also known as EGFR-sensitive mutations). Currently, three generations of EGFR small molecule inhibitors are approved for the treatment of EGFR-mutant NSCLC patients. First- and second-generation EGFR inhibitors, such as gefitinib, erlotinib, afatinib, and dacomitinib, have achieved great success in the treatment of NSCLC. However, they have significant side effects such as rash and diarrhea, and patients develop drug resistance after one year of use. Clinical data shows that approximately 50% of patients acquire resistance due to the T790M mutation (threonine is replaced by methionine at position 790 in exon 20).

[0005] Third-generation EGFR inhibitors, such as osimertinib, are irreversible inhibitors that covalently bind to C797, significantly enhancing their activity. They can be used as second-line treatment for patients with EGFR T790M mutations after treatment with first- or second-generation EGFR inhibitors, or as first-line treatment for patients with EGFR-sensitive mutations. However, when osimertinib is used as second-line treatment for EGFR T790M-mutant patients, C797X triple resistance mutations (cysteine ​​at exon 20, position 797, mutated to serine or glycine, etc.) inevitably develop after 9.9-10.1 months of treatment.

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

[0007] Osimertinib, as a first-line treatment, has shown good efficacy compared to 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, 7% of 91 patients who developed resistance to osimertinib were found to have C797S dual resistance mutations.

[0008] For patients with EGFR-sensitive mutations, the best recommended first-line treatment is the use of third-generation EGFR inhibitors such as osimertinib. Therefore, C797X dual resistance mutations inevitably develop after a period of osimertinib use. Currently, no drugs are approved for the treatment of lung cancer carrying EGFR C797X resistance mutations. Clinical trials have shown that drugs targeting EGFR C797X resistance mutations have poor efficacy and a high incidence of adverse reactions such as rash and diarrhea. Furthermore, the risk of brain metastasis increases annually in lung cancer patients with EGFR mutations, with an overall probability of 50-70% throughout the disease course. Brain metastasis is one of the leading causes of death in lung cancer patients.

[0009] In conclusion, there is an unmet clinical need for EGFR drugs, and it is of great significance to develop a fourth-generation EGFR inhibitor that can target both EGFR-sensitive and EGFR-resistant mutations and can cross the blood-brain barrier. Summary of the Invention

[0010] To address the shortcomings of existing technologies, this invention aims to provide a heteroaryl macrocyclic compound, its preparation method, and its applications. This heteroaryl macrocyclic compound exhibits good EGFR mutation-inhibiting activity and can cross the blood-brain barrier.

[0011] The present invention is achieved through the following technical solution.

[0012] In a first aspect, the present invention provides a heteroaryl macrocyclic compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate or solvate thereof.

[0013] In Equation I,

[0014] Ring A is a 5-14-membered heteroaryl, a 3-12-membered heterocyclic, or a 6-12-membered aryl, wherein the 5-14-membered heteroaryl, 3-12-membered heterocyclic, or 6-12-membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1 replace;

[0015] The E ring is a 5-14-membered heteroaryl, 6-12-membered aryl, or 3-12-membered heterocyclic group, wherein the 5-14-membered heteroaryl, 6-12-membered aryl, or 3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace;

[0016] The M ring is a 5-14-membered heteroaryl, 6-12-membered aryl, 3-12-membered heterocyclic, 3-12-membered cycloalkyl, or 3-12-membered cycloalkenyl group, wherein the 5-14-membered heteroaryl, 6-12-membered aryl, 3-12-membered heterocyclic, 3-12-membered cycloalkyl, or 3-12-membered cycloalkenyl group is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace;

[0017] L1 represents chemical bonds, NH, CH2, O, S, C=O, or S(=O)(W 1 The NH and CH2 are optionally separated by one or two identical or different R atoms. 4 replace;

[0018] L2 is C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl group, containing 1-3 radicals selected from N, O, S, S(=O)(W 1 C atoms 1-10 Heteroalkylene groups, containing 1-3 ions selected from N, O, S, S(=O)(W 1 C atoms 2-10 Heteroeneyl, 3-12 membered heterocyclic group -C 0-6Alkyl, 3-12 membered cycloalkyl-C 0-6 Alkyl, C 1-6 alkyl-3-12-membered heterocyclic-C 0-6 Alkyl or C 1-6 Alkyl-3-12-membered cycloalkyl-C 0-6 Alkyl, the C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl group, containing 1-3 radicals selected from N, O, S, S(=O)(W 1 C atoms 1-10 Heteroalkylene groups, containing 1-3 ions selected from N, O, S, S(=O)(W 1 C atoms 2-10 Heteroeneyl, 3-12 membered heterocyclic group -C 0-6 Alkyl, 3-12 membered cycloalkyl-C 0-6 Alkyl, C 1-6 alkyl-3-12-membered heterocyclic-C 0-6 Alkyl, C 1-6 Alkyl-3-12-membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace;

[0019] X1, X2, and X3 are each an independent chemical bond, NR 1a -C(R) 2a (R) 3a )-, O, S, C (=O) or S (=O)(W 1 );

[0020] R 1 Hydrogen atom, deuterium atom, halogen, CN, NO2, amino, hydroxyl, 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 The amino, hydroxyl, and 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 Re2 It can be optionally replaced by one or more R′;

[0021] R 2 R 3 Each can be independently represented as a hydrogen atom, a deuterium atom, a halogen, CN, NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR 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 C 0-6 Alkyl-S(=O)(W 1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)Re1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1- 6-alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)(W 1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0022] Or, two Rs 2 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0023] Or, X1 and R 2Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0024] Or, two Rs 3 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0025] Or, X2 and R 3 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0026] R 4 Each is independently a hydrogen atom, deuterium atom, halogen, or carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl may be optionally substituted by one or more R′;

[0027] R 5 Each can be independently represented as a hydrogen atom, a deuterium atom, a halogen, CN, NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C1-6 Alkyl, 5-10 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 R e2 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′;

[0028] Or, two Rs 5 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups are optionally substituted by one or more R′.

[0029] R 1a R 2a Each is independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 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 R e2 C(=O)OR e1 S(=O)(W) 1 )NR e1 R e2 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 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more R′;

[0030] R 3a Hydrogen atom, deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 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 e1OS(=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 R e2 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more R′;

[0031] Or, R 2a and R 3a Together with their respective C atoms, they form 3-12 membered cycloalkyl or 3-12 membered heterocyclic groups, which are optionally substituted by one or more R′;

[0032] R′ represents a deuterium atom, halogen, CN, NO2, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, ORf1 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 C 0- 6-alkyl-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 R f2 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 oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″;

[0033] R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 aryl or C 0-6 alkyl-5-10 heteroaryl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 aryl, C 0-6 Alkyl-5-10 heteroaryl groups are optionally surrounded by one or more R″;

[0034] Or, R e1 and R e2 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0035] Or, R e2 and R e3 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0036] Or, R f1 and R f2 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0037] R″ represents deuterium, halogen, CN, NO2, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 OC(=O)R g1 OC (=O)NR g1 R g2 OS(=O)R g1 OS(=O)(W) 1 )R g1 OS(=O)NR g1 R g2 OS(=O)(W) 1 )NR g1 R g2 SR g1 S(=O)R g1 S(=O)(W) 1 )R g1 S(=O)NR g1 R g2 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 S(=O)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 g2P(=O)2R g1 R g2 P(=O)OR g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more of the following groups: deuterium, halogen, CN, hydroxyl, amino, C. 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ;

[0038] R g1 R g2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl or 3-12 membered heterocyclic, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 The alkenyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group may optionally be substituted by one or more of the following groups: deuterium atom, halogen, CN, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkyl groups, 3-12 membered cycloalkoxy groups;

[0039] W 1 =None, =O or =NR g1 .

[0040] In some embodiments, in Formula I, the compound further has the structure shown in Formula II:

[0041] The definitions of A, E, M, X1, X2, and L2 are as described above.

[0042] In some embodiments, in Formula I or II, ring A is a 5-10-membered heteroaryl or a 6-10-membered aryl, wherein the 5-10-membered heteroaryl or 6-10-membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1 replace;

[0043] Optionally, ring A is Optionally, 1, 2, 3, or 4 identical or different R... 1 Replace, among which,

[0044] Indicates a single bond or a double bond;

[0045] Z 1 Z 2 Each can be independently N, NH, CH, O, S, C=O or S(=O)(W 1 );

[0046] Z 3 Z 4 Z 5 Each can be either N or CH independently;

[0047] Z 6 Z 7 Z 8 Each can be N or C independently;

[0048] Further, alternatively, ring A is selected from the following groups:

[0049] Among them, R 1a′ R 1b′ R 1c′ R 1d′ R 1e′ Each independently as R 1 ;

[0050] Optionally, R 1 For hydrogen atoms, deuterium atoms, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, hydroxyl, cyano, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, CHO or C(=O)NH2, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6Alkyl)2amino, CHO or C(=O)NH2 is optionally substituted with one or more deuterium atoms, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, methoxy, ethoxy, isopropoxy, cyclopropoxy;

[0051] Further optional, R 1 It can be hydrogen atom, deuterium atom, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trideutermethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, ethylene, propylene, acetylene, propyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, cyano, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, methoxy, ethoxy, cyclopropoxy, oxo, CHO or C(=O)NH2.

[0052] In some embodiments, in Formula I or II, the E ring is a 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group, wherein the 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace;

[0053] Optionally, ring E is The Optionally, 1, 2, 3, or 4 identical or different R... 2 Replace; among them,

[0054] Indicates a single bond or a double bond;

[0055] The B ring is absent or is a 5-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a 6 membered aryl group;

[0056] Y 1 Y 2 Each can be independently N, NH, CH or CH2;

[0057] Y 3 For N, NH, C, CH or CH2; when Y 3 When fused with the B ring, Y 3 For N, C or CH;

[0058] Y 4 Y 5 Each can be independently N, C, or CH;

[0059] Optionally, the E ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace:

[0060] Further, alternatively, the E ring is selected from the following groups:

[0061] Among them, R 2a′ R 2b′ R 2c′ R 2d′ R 2e′ R 2f′ Each independently as R 2 .

[0062] In some embodiments, in Formula I or II, the M ring is a 5-6 membered heteroaryl, a 9-10 membered heteroaryl, or a 6 membered aryl, wherein the 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 6 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 3 replace;

[0063] Optionally, the M ring is benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole, wherein the benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace;

[0064] Optionally, the M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace:

[0065] Further optionally, the M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 3 replace:

[0066] Optionally, R 3 Hydrogen atom, deuterium atom, halogen, CN, hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 , oxo, C(=O)R e1 C(=O)NR e1 R e2 Or S(=O)(W) 1 )R e1 The hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-ORe1 It can be optionally replaced by one or more R′;

[0067] Or, two Rs 3 Together with the atoms they are attached to, they form 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups, wherein the 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups are optionally substituted by one or more R′.

[0068] Or, X2 and R 3 Together with the connected atoms, they form 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups, wherein the 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally substituted by one or more R′.

[0069] Optionally, R e1 R e2 Each of them independently is methyl, ethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0070] Further optional, R 3 For hydrogen atom, deuterium atom, F, Cl, Br, I, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trideuterated methyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl;

[0071] Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution.

[0072] In some embodiments, in Formula I or II, L1 is a chemical bond or NR. 4 ;

[0073] Optionally, L1 is a chemical bond or NH.

[0074] In some implementations, in formula I or II, L2 is C 1-6 Alkylene, C1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace;

[0075] Optionally, R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′;

[0076] Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′;

[0077] Optionally, L2 is ethylidene, propyleneidene, butylidene, pentylene, hexylidene, oxapropyleneide, oxabutylidene, azidopropyleneide, azidobutylidene, propenylidene, or butenylidene, wherein the ethylidene, propyleneidene, butylidene, pentylene, hexylidene, oxapropyleneide, oxabutylidene, azidopropyleneide, azidobutylidene, propenylidene, or butenylidene is optionally surrounded by one or more identical or different R... 5 replace.

[0078] Optionally, R 5 The hydroxyl group, deuterium group, F, Cl, Br, CN, hydroxyl group, hydroxyethyl group, amino group, methylamino group, dimethylamino group, cyclopropylamino group, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziroxybutyl group, aziroxypentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, cyclopropoxy group, or oxo group may be optionally substituted with one or more of the same or different F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclopentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, or cyclopropoxy group;

[0079] Or, two Rs 5 Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, and homomorpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, and homomorpholinyl groups are optionally substituted by one or more of the same or different F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, and methoxy groups.

[0080] Optionally, L2 is selected from the following groups:

[0081] In some implementations, X1 in formula I or II is NR 1a -C(R) 2a (R) 3a )- or O.

[0082] In some implementations, X2 is NR in formula I or II. 1a -C(R) 2a (R) 3a )- or O.

[0083] In some embodiments, in Formula I or II, X3 is a chemical bond, NR 1a -C(R) 2a (R) 3a - or O;

[0084] Optionally, X3 is a chemical bond.

[0085] In some implementations, R 1 Hydrogen atom, deuterium atom, halogen, CN, NO2, hydroxyl, amino, 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, (C=O)R e1 Or C(=O)NR e1 R e2 The amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more R′;

[0086] Optionally, R 1 Each is independently a hydrogen atom, deuterium atom, halogen, or carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, hydroxyl, cyano, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, CHO or C(=O)NH2, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, CHO, C(=O)NH2 are optionally substituted by one or more F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxy, cyano, methoxy, ethoxy, isopropoxy, cyclopropoxy;

[0087] Further optional, R 1It can be hydrogen atom, deuterium atom, F, Cl, Br, CN, cyano, hydroxyethyl, hydroxyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, cyclopropoxy, trifluoromethoxy, trifluoroethoxy, vinyl, propynyl, ethynyl, propynyl, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl or C(=O)N(CH3)2.

[0088] In some implementations, R 2 Each can be independently represented as a hydrogen atom, deuterium atom, halogen, CN, nitro group, or C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 S(=O)(=NR) g1 )R e1 C 0- 6-alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0- 6-alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0089] Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′.

[0090] Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′;

[0091] Optionally, R 2 Each is independently a hydrogen atom, deuterium atom, halogen, CN, nitro, C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1- 3-alkyl, 5-6-membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 S(=O)(=NR) e2 )R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0- 3-alkyl-3-6-membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0092] Further optional, R 2 Each of these groups can be independently a hydrogen atom, deuterium atom, halogen, nitro group, hydroxyl group, CN group, methyl group, ethyl group, isopropyl group, trideuterated methyl group, difluoromethyl group, trifluoromethyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, difluoroethoxy group, trifluoroethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, mercapto group, methyl mercapto group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or selected from the following groups:

[0093] Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups;

[0094] Or, X1 and R 2Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN groups, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups.

[0095] In some implementations, R 3 Each can be independently represented as a hydrogen atom, deuterium atom, halogen, CN, nitro group, or C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 S(=O)(=NR) g1 )R e1 C 0- 6-alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)Re1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0- 6-alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0096] Or, two Rs 3 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0097] Or, X2 and R 3 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups are optionally substituted by one or more R′.

[0098] Optionally, R 3 Hydrogen atom, deuterium atom, halogen, CN, hydroxyl group, C 1-6 Alkyl, NRe1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 , oxo, C(=O)R e1 C(=O)NR e1 R e2 Or S(=O)(W) 1 )R e1 The hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 It can be optionally replaced by one or more R′;

[0099] Or, two Rs 3 Together with the atoms they are attached to, they form 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups, wherein the 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups are optionally substituted by one or more R′.

[0100] Or, X2 and R 3 Together with the connected atoms, they form 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups, wherein the 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally substituted by one or more R′.

[0101] Further optional, R 3 For hydrogen atom, deuterium atom, F, Cl, Br, I, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trideuterated methyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl;

[0102] Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution.

[0103] In some implementations, R 4 For hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl groups and 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0104] Optionally, R 4 It is a hydrogen atom.

[0105] In some implementations, R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0- The 3-alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′;

[0106] Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′;

[0107] Further optional, R 5The hydroxyl group, deuterium group, F, Cl, Br, CN, hydroxyl group, hydroxyethyl group, amino group, methylamino group, dimethylamino group, cyclopropylamino group, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziroxybutyl group, aziroxypentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, cyclopropoxy group, or oxo group may be optionally substituted with one or more of the same or different F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclopentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, or cyclopropoxy group;

[0108] Or, two Rs 5 Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, and homomorpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, and homomorpholinyl groups are optionally substituted by one or more of the same or different F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, and methoxy groups.

[0109] In some implementations, R 1a For hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0110] Optionally, R 1a For hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0111] Further optional, R 1a It can be a hydrogen atom, a deuterium atom, a methyl atom, an ethyl atom, an isopropyl atom, a cyclopropyl atom, a cyclobutyl atom, a cyclopentyl atom, a cyclohexyl atom, a trideuterated methyl atom, a difluoromethyl atom, a trifluoromethyl atom, a difluoroethyl atom, a trifluoroethyl atom, or a hydroxyethyl atom.

[0112] In some implementations, R2a For hydrogen atoms, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0113] Optionally, R 2a It consists of hydrogen atoms, deuterium atoms, halogens, cyano groups, and carbon atoms. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0114] Further optional, R 2a It can be a hydrogen atom, a deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl.

[0115] In some implementations, R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, 3-10 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino groups and 3-10-membered heterocyclic groups are optionally substituted with one or more R′ groups;

[0116] Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′;

[0117] Optionally, R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, 3-7 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 The alkyl)amino group and the 3-7 membered heterocyclic group are optionally substituted with one or more R′ groups;

[0118] Further optional, R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy;

[0119] Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′.

[0120] In some embodiments, R′ is a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-6 Alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″;

[0121] Optionally, R′ can be a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-3 Alkyl-S(=O)(W 1 )R f1 S(=O)(W)1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1- 6-alkyl, 3-6-membered cycloalkyl, 3-12-membered heterocyclic, C 0-3 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″;

[0122] Further optionally, R′ can be a deuterium atom, F, Cl, Br, CN, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, aziridine, aziridine, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, methoxy, ethoxy, cyclopropoxy, hydroxy, hydroxyethyl, S(=O)-methyl, S(=O)2-methyl, S(=O)(=NH)-methyl S(=O)2-cyclopropyl, methyl-S(=O)-methyl, methyl-S(=O)2-methyl, methyl-S(=O)2-cyclopropyl, amino, methylamino, dimethylamino, cyclopropylamino, C(=O)O-methyl, C(=O)-methyl, NHS(=O)2-methyl, N(methyl)S(=O)2-methyl, N(cyclopropyl)S(=O)2-methyl, NHS(=O)2-cyclopropyl, N(methyl)S(=O)2-cyclopropyl The group consisting of methyl, ethyl, isopropyl, difluoromethyl, difluoroethyl, trifluoroethyl, aziridine, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, methoxy, ethoxy, cyclopropoxy, hydroxy, hydroxyethyl, S(=O)-methyl, S(=O)2-methyl, S(=O)(=NH)-methyl, S(=O)2-cyclopropyl, methyl-S(=O) )-methyl, methyl-S(=O)2-methyl, methyl-S(=O)2-cyclopropyl, amino, methylamino, dimethylamino, cyclopropylamino, C(=O)O-methyl, C(=O)-methyl, NHS(=O)2-methyl, N(methyl)S(=O)2-methyl, N(cyclopropyl)S(=O)2-methyl, NHS(=O)2-cyclopropyl, N(methyl)S(=O)2-cyclopropyl, cyclopropyl is optionally substituted by one or more R″.

[0123] In some implementations, R e1 R e2R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 5-10 membered heteroaryl are optionally substituted by one or more R″;

[0124] Optionally, R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic or 5-6 membered heteroaryl, said C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, and 5-6 membered heteroaryl may optionally be substituted by one or more R″;

[0125] Further optional, R e1 R e2 R e3 R f1 R f2 Each of the following is independently represented as a hydrogen atom, deuterium atom, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, aziridine, oxazolyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and the aforementioned methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, and difluoroethyl Trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, aziridine, oxaziridine, oxaziridine, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl are optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, oxo, C(=O)-methyl or C(=O)-ethyl.

[0126] In some implementations, R″ is a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkoxy, cyano, or oxo substitution;

[0127] Optionally, R″ is a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic groups optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkoxy, cyano, or oxo substitution;

[0128] Further optionally, R″ is a deuterium atom, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, S(=O)2methyl, S(=O)2ethyl, S(=O)2cyclopropyl, or oxo, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, S(=O)2methyl, S(=O)2ethyl, or S(=O)2cyclopropyl is optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, oxo, C(=O)-methyl, or C(=O)-ethyl.

[0129] In some implementations, R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, or C(=O)C 1-3 Alkyl substitution;

[0130] Optionally, R g1 R g2 Each of the following is independently a hydrogen atom, methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, oxo, C(=O)-methyl, or C(=O)-ethyl.

[0131] In some implementations, W 1 =None, =O or =NR g1 .

[0132] In some specific implementations, in formula I or II:

[0133] Ring A is a 5-10 membered heteroaryl or a 6-10 membered aryl, wherein the 5-10 membered heteroaryl or 6-10 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1replace;

[0134] The E ring is a 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group, wherein the 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace;

[0135] The M ring is a 5-6 membered heteroaryl, a 9-10 membered heteroaryl, or a 6 membered aryl, wherein the 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 6 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace;

[0136] L1 is a chemical bond or NR 4 ;

[0137] L2 is C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace;

[0138] X1 is NR 1a -C(R) 2a (R) 3a - or O;

[0139] X2 is NR 1a -C(R) 2a (R) 3a - or O;

[0140] X3 is a chemical bond, NR 1a -C(R) 2a (R) 3a - or O;

[0141] R 1 Hydrogen atom, deuterium atom, halogen, CN, NO2, amino, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 The amino, hydroxyl, and 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 It can be optionally replaced by one or more R′;

[0142] R 2 R 3 Each can be independently represented as a hydrogen atom, deuterium atom, halogen, CN, nitro group, or C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 S(=O)(=NR) g1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0- 6-alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0143] Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′.

[0144] Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′;

[0145] Or, two Rs 3 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, and 6-14-membered aryl groups are optionally substituted by one or more R′.

[0146] Or, X2 and R 3 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, and 6-14-membered aryl groups are optionally substituted by one or more R′.

[0147] R 4 It is a hydrogen atom;

[0148] R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′;

[0149] Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′;

[0150] R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C1-6 Alkyl or 3-12 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0151] R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1- 6-alkyl)amino or 3-10 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino groups and 3-10-membered heterocyclic groups are optionally substituted with one or more R′ groups;

[0152] Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′;

[0153] R′ represents a deuterium atom, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-6 Alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″;

[0154] R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic and 5-10 membered heteroaryl are optionally substituted by one or more R″;

[0155] R″ represents deuterium, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group optionally surrounded by one or more halogens, hydroxyl groups, C 1- 6-alkyl, halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, cyano, and oxo substitutions;

[0156] R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, or C(=O)C 1- 3-alkyl substitution;

[0157] W 1 =None, =O or =NR g1 .

[0158] In other specific embodiments, in formula I or II:

[0159] Ring A is Optionally, 1, 2, 3, or 4 identical or different R... 1 Replace, among which,

[0160] Indicates a single bond or a double bond;

[0161] Z 1 Z 2 Each can be independently N, NH, CH, O, S, C=O or S(=O)(W 1 );

[0162] Z 3 Z 4 Z 5 Each can be either N or CH independently;

[0163] Z 6 Z 7 Z 8 Each can be N or C independently;

[0164] E ring is The Optionally, 1, 2, 3, or 4 identical or different R... 2 Replace; among them,

[0165] Indicates a single bond or a double bond;

[0166] The B ring is absent or is a 5-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a 6 membered aryl group;

[0167] Y 1 Y 2 Each can be independently N, NH, CH or CH2;

[0168] Y 3 For N, NH, C, CH or CH2; when Y 3 When fused with the B ring, Y 3 For N, C or CH;

[0169] Y 4 Y 5 Each can be independently N, C, or CH;

[0170] The M ring is benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole, wherein the benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace;

[0171] L1 represents a chemical bond or NH;

[0172] L2 is C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace;

[0173] X1 is NR 1a -C(R) 2a (R) 3a - or O;

[0174] X2 is NR 1a -C(R) 2a (R) 3a - or O;

[0175] X3 is a chemical bond;

[0176] R 1 Each is independently a hydrogen atom, deuterium atom, halogen, or carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, hydroxyl, cyano, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, CHO, C(=O)NH2, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, CHO, C(=O)NH2 are optionally substituted by one or more F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxy, cyano, methoxy, ethoxy, isopropoxy or cyclopropoxy;

[0177] R 2 Each is independently a hydrogen atom, deuterium atom, halogen, CN, nitro, C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 S(=O)(=NR) e2 )R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 、or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1- 3-alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SRe1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′;

[0178] R 3 Hydrogen atom, deuterium atom, halogen, CN, hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 , oxo, C(=O)R e1 C(=O)NR e1 R e2 Or S(=O)(W) 1 )R e1 The hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 It can be optionally replaced by one or more R′;

[0179] Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′.

[0180] Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′;

[0181] Or, two Rs 3Together with the atoms they are attached to, they form 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups, wherein the 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups are optionally substituted by one or more R′.

[0182] Or, X2 and R 3 Together with the connected atoms, they form 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups, wherein the 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally substituted by one or more R′.

[0183] R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′;

[0184] Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′;

[0185] R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′;

[0186] R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1- 6-alkyl)amino, 3-7 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 The alkyl)amino group and the 3-7 membered heterocyclic group are optionally substituted with one or more R′ groups;

[0187] Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′;

[0188] R′ represents a deuterium atom, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-3 Alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-3 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″;

[0189] R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic or 5-6 membered heteroaryl, said C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic and 5-6 membered heteroaryl groups are optionally substituted by one or more R″;

[0190] R″ represents deuterium, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic groups optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkoxy, cyano, or oxo substitution;

[0191] R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, or C(=O)C 1- 3-alkyl substitution;

[0192] W 1 =None, =O or =NR g1 .

[0193] In some other specific embodiments, in formula I or II:

[0194] Ring A is selected from the following groups:

[0195] The E ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace:

[0196] The M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace:

[0197] L1 represents a chemical bond or NH;

[0198] L2 is ethylene, propyleneene, butylene, pentylene, hexylene, oxapropyleneene, oxabutylene, aziridine, aziridine, propenylene, or butenylene, wherein the ethylene, propyleneene, butylene, pentylene, hexylene, oxapropyleneene, oxabutylene, aziridine, aziridine, propenylene, or butenylene is optionally surrounded by one or more identical or different R groups. 5 replace;

[0199] X1 is NR 1a -C(R) 2a (R) 3a - or O;

[0200] X2 is NR 1a -C(R) 2a (R) 3a - or O;

[0201] X3 is a chemical bond;

[0202] R 2 Each of these groups can be independently a hydrogen atom, deuterium atom, halogen, nitro group, hydroxyl group, CN group, methyl group, ethyl group, isopropyl group, trideuterated methyl group, difluoromethyl group, trifluoromethyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, difluoroethoxy group, trifluoroethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, mercapto group, methyl mercapto group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or selected from the following groups:

[0203] Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups;

[0204] Or, X1 and R 2Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN groups, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups.

[0205] R 3 For hydrogen atom, deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl;

[0206] Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution;

[0207] R 5 The hydroxyl group, deuterium group, F, Cl, Br, CN, hydroxyl group, hydroxyethyl group, amino group, methylamino group, dimethylamino group, cyclopropylamino group, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziroxybutyl group, aziroxypentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, cyclopropoxy group, or oxo group may be optionally substituted with one or more of the same or different F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclopentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, or cyclopropoxy group;

[0208] Or, two Rs 5 Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, or homomorpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl, or homomorpholinyl groups are optionally substituted with one or more of the same or different F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, or methoxy groups;

[0209] R 1a R 2a Each can be independently a hydrogen atom, deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl;

[0210] R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy;

[0211] Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′ groups.

[0212] R′ can be a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, or oxo.

[0213] R g1 The methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl groups are optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, or oxo groups.

[0214] W 1 =None, =O or =NR g1 ;

[0215] R 1a′ R 1b′ R 1c′ R 1d′ R 1e′ Each independently as R 1 ;R 1 It can be hydrogen atom, deuterium atom, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, ethylene, propylene, acetylene, propyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, cyano, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, methoxy, ethoxy, cyclopropoxy, oxo, CHO or C(=O)NH2.

[0216] In some other specific embodiments, in formula I or II:

[0217] Ring A is selected from the following groups:

[0218] The E ring is selected from the following groups:

[0219] The M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace:

[0220] L1 represents a chemical bond or NH;

[0221] L2 is selected from the following groups:

[0222] X1 is NR 1a -C(R) 2a (R) 3a - or O;

[0223] X2 is NR 1a -C(R) 2a (R) 3a - or O;

[0224] X3 is a chemical bond;

[0225] R 2a′ R 2b′ R 2c′ R 2d′ R 2e′ R 2f′ Each independently as R 2 ;

[0226] R 2It can be a hydrogen atom, deuterium atom, halogen, nitro, hydroxyl, CN, methyl, ethyl, isopropyl, trideuterated methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, mercapto, methylmercapto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or selected from the following groups:

[0227] Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups;

[0228] Or, X1 and R 2 Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN groups, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups.

[0229] R 3 For hydrogen atom, deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl;

[0230] Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution;

[0231] R 1a R 2a Each can be independently a hydrogen atom, deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl;

[0232] R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy;

[0233] Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′ groups;

[0234] W 1 =None, =O or =NR g1 ;

[0235] R g1 R g2 Each of the following is independently a hydrogen atom, methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, or oxo.

[0236] In a more specific embodiment, the compound represented by Formula I is selected from the following compounds:

[0237] In a second aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate or solvate and a pharmaceutically acceptable carrier or excipient.

[0238] Optionally, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, or spray.

[0239] Thirdly, the present invention provides the use of the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope labels, deuterated derivatives, N-oxides, prodrug molecules, hydrates or solvates thereof, or pharmaceutical compositions comprising the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope labels, deuterated derivatives, N-oxides, prodrug molecules, hydrates or solvates thereof, and pharmaceutically acceptable carriers or excipients in the preparation of medicaments for treating EGFR-mediated diseases;

[0240] Optionally, the disease is a neoplastic disease;

[0241] Further optionally, the neoplastic diseases include: head and neck cancer, nasopharyngeal carcinoma, 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.

[0242] Fourthly, the present invention provides a method for treating tumors in patients in need, the method comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate or solvate or pharmaceutical composition thereof.

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

[0244] In some embodiments, the administration route includes: oral, mucosal, sublingual, ocular, local, parenteral, rectal, cisternae dorsalis, vaginal, peritoneal, bladder, and nasal administration.

[0245] In some embodiments, the tumor includes: 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, cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.

[0246] The compounds involved in this invention, or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope labels, deuterated derivatives, N-oxides, prodrug molecules, hydrates or solvates, or pharmaceutical compositions, may enter the body through any suitable route, such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.

[0247] In some embodiments, the compounds provided in this invention, or their pharmaceutically acceptable salts, stereoisomers, racemates, tautomers, isotope labels, deuterated derivatives, N-oxides, prodrug molecules, hydrates or solvates, or pharmaceutical compositions, can be formulated into dosage forms suitable for drug release, administered via injection routes (e.g., subcutaneous, intravenous, intra-articular, sheath, intracapsular, intra-frame, intracardiac, intradermal, intraperitoneal, tracheal, epidermal, intra-articular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes (e.g., oral, enteric, oral, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal, or topical epidermal administration).

[0248] 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, sugar-coated pills, powders, and granules; dosage forms for topical or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, medicated patches, and inhalers; 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 appropriate conditions, and the methods and processes for preparation 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).

[0249] In some implementations, EGFR abnormality refers to EGFR mutation, EGFR amplification, or EGFR overexpression.

[0250] Optionally, EGFR mutations refer to the deletion, alteration, and / or insertion of other amino acids at any position in the EGFR sequence. They generally occur in intracellular exons 18-21 or extracellular exons 2-16.

[0251] Further, optionally, 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 insertions in exon 19 such as delE746_A750, delE746_E749, A750P, delE746_A750insQP, delE746_A750insRP, etc.; and exon 20... Point mutations and insertion mutations, such as S768I, V769_D770insASV, D770_N771insSVD, D770_N771insG, A763_Y764insFQEA, etc., exon 21 point mutations, such as L858R, L861Q / R, etc., also include secondary resistance mutations such as T790M, L792H, G796R / S / D, C797S / G / N, L718P / Q / V, etc. In addition, EGFR mutations also include combinations of these mutations.

[0252] In some embodiments, the compounds or pharmaceutical compositions of the present invention can be administered simultaneously with one or more substances having additional pharmacological activity, thereby achieving synergistic or even additive effects in vivo. For example, the compounds of the present invention can be combined with substances having additional pharmacological activity to form a pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions. Other pharmacologically active substances that can be simultaneously administered with the compounds of this invention for the treatment of cancer include, but are not limited to: 1) EGFR family inhibitors, monoclonal / biclonal antibodies or ADCs, such as osimertinib, amitinib, vormetinib, befotinib, olmutinib, lazertinib, PLB1004, afatinib, dacomitinib, erlotinib, gefitinib, icotinib, cetuximab, panitumumab, amivantamab, lapatinib, neratinib, tucatinib, trastuzumab, pertuzumab, margetuximab, trastuzumab emtansine, detrastuzumab, etc.; 2) downstream pathway or other pathway target inhibitors, monoclonal / biclonal antibodies or ADCs, etc., wherein the targets include, but are not limited to, MEK, RET, PI3K, mTOR, c-Met, PARP or mitotic kinase inhibitors (such as CDK4 / 6), etc.Examples include: trametinib, bimetinib, seletinib, peracitinib, edralib, copanlisib, duvelisib, alpelisib, umbralisib, parsaclisib, rapamycin, tesirobolimus, everolimus, carmatinib, terpoxtinib, cevotinib, gumetinib, beritinib, cabozantinib, emibetuzumab, telisotuzumab, nirapaib, palbocicib, rebocicib, abemaciclib, etc. 3) Anti-angiogenic drugs, such as bevacizumab, aflibercept, ramucirumab, nintedanib, etc.; 4) Apoptosis inducers (such as Bcl-2), such as obatoclax, veneclax, etc.; 5) Chemotherapy drugs, such as fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprorelin, goserelin, flutamide, nilumethicone, finasteride, dexamethasone, aminoglutide, acridine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, cisplatin, etc. Mustard, Chloramic Acid Mustard, Cladribine, Colchicine, Cyclophosphamide, Cyproterone Acid, Cytarabine, Dacarbazine, Diethylstilbestrol, Diethylstilbestrol, Docetaxel, Doxorubicin, Adriamycin, Epirubicin, Estradiol, Estronemustine, Etoposide, Exemestane, Filgrass, Fludarabine, Fludrocortisone, Flumethasone, Flutamiflu, Gemcitabine, Goserelin, Teniposide, Testosterone, Dichlorophenoxyacetate, Toptraconazole, Retinoic Acid, Vinpocetine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Letrozole Azole, leucovorin, pentostatin, photomycin, procarbazine, raltitrexed, porphyrin sodium, rituximab, streptozotocin, suramin, leuprorelin, levamisole, cyclohexanenitrosourea, nitrogen mustard, medroxyprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, sodium thiosulfate, methotrexate, mitomycin, mitotane, mitoxantrone, nilumethicone, nocodazole, octreotide, paclitaxel, pamidronate, thioguanine, thiamethoxam, chloromethane, topotecan, retinoic acid, vinblastine, vincristine, vindesine, vinorelbine, pemetrexed.

[0253] In some embodiments, the compounds provided by this invention can be used concurrently with immunotherapeutic agents. Suitable immunotherapeutic agents include: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors such as durvalumab; tumor cell multidrug resistance reversal agents (such as verapamil), mycophenolate mofetil, thalidomide, cyclosporine, and monoclonal antibodies.

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

[0255] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0256] It is particularly important to note that similar substitutions and modifications made to this invention are obvious to those skilled in the art, and they are all considered to be included in this invention. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments.

[0257] Unless otherwise specified, this invention is carried out under conventional conditions or conditions recommended by the manufacturer. The raw materials or excipients used, as well as the reagents or instruments used, whose manufacturers are not specified, are all conventional products that can be obtained commercially.

[0258] Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and scope of various terms used to describe the invention.

[0259] Indicates the connection site.

[0260] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, C a-b Alkyl, prefix C a-b This represents any number of carbon atoms from "a" to "b". (C) a-b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). Therefore, for example, C 0-6 Alkyl groups are alkyl groups containing 0 to 6 carbon atoms. An alkyl group with 0 carbon atoms is equivalent to having none. 1-10 Alkyl refers to an alkyl group containing 1 to 10 carbon atoms. The alkyl group may be branched or straight-chain.

[0261] The atoms described in the compounds of this invention include their isotopes; for example, hydrogen may be deuterium or tritium.

[0262] A "bridged ring" refers to a polycyclic group in which two or more monocyclic rings share two non-directly connected atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The ring atoms can be all carbon atoms or one or more of the ring atoms can be selected from N, O, S, S(=O) or S(=O)2. It is preferably a 7-10 membered ring.

[0263] "Spirocyclic" refers to a polycyclic group in which any two or more monocyclic rings share a single carbon atom. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The ring atom can be an all-carbon atom or one or more of the ring atoms can be selected from N, O, S, S(=O) or S(=O)2. 5-14 membered spirocyclic rings include, but are not limited to, 5- to 14-membered spirocyclic rings, with 7- to 11-membered spirocyclic rings being preferred.

[0264] A "fused ring" is a polycyclic group consisting of two or more monocyclic rings sharing two adjacent atoms. A "linked ring" is a polycyclic group consisting of two or more monocyclic rings connected by chemical bonds.

[0265] The bridging ring, spiro ring, fused ring, and linked ring can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.

[0266] A cyclic group can be bonded to another group in multiple ways. If the bonding mode is not specified, it means that all possible modes are included. For example, "pyridinyl" includes 2-, 3-, or 4-pyridinyl, while "thiophene" includes 2- or 3-thiophene.

[0267] "alkyl" refers to a straight-chain or branched, monovalent saturated aliphatic 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, and other similar groups. C is preferred. 1-10 Alkyl group. More preferably, C10. 1-6 Alkyl group. More preferably, C10. 1-4 Alkyl group. The term "alkyl" is monovalent, divalent, or trivalent, and the valence can be on the same atom or on two different atoms. The alkyl group includes alkylene groups. The alkyl group may optionally be substituted by one or more substituents described in this application. When substituted, the substituent can be attached at any connection point. The substituents are: deuterium, halogen, CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6Alkyl-3-12 saturated or unsaturated cycloalkyl, -C 0-6 Alkyl-3-12 saturated or unsaturated heterocyclic groups, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -C 0-6 Alkyl-6-10 aryl, -C 0-6 Alkyl-5-10 heteroaryl, oxo (=O), -C 0-6 Alkyl-OR e1 -C 0-6 Alkyl-SR e1 -C 0-6 Alkyl-S(=O)R e1 -C 0-6 Alkyl-S(=O)2R e1 -C 0-6 Alkyl-C(=O)R e1 -C 0-6 Alkyl-C(=O)NR e1 R e2 -C 0-6 Alkyl-C(=O)OR e1 -C 0-6 Alkyl-NR e1 R e2 -C 0-6 Alkyl-NR e1 C(=O)R e2 -C 0-6 Alkyl-OC(=O)R e1 -C 0-6 Alkyl-S(=O)NR e1 R e2 -C 0-6 Alkyl-S(=O)2NR e1 R e2 -C 0-6 Alkyl-NHS(=O)2R e1 -C 0-6 Alkyl-NHS(=O)R e1 -C 0-6 Alkyl-NR e1 C(=O)OR e2 -C 0-6 Alkyl-NR e1 C(=O)NR e2 -C 0-6 Alkyl-(O)(OR) e1 )2、-C 0-6 Alkyl-P(O)(R) e1 )2 or oxygen (=O).

[0268] The substituents are preferably the following groups: deuterium atom, halogen, cyano, nitro, azide, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Heteroalkenyl, 3-12 saturated or unsaturated cycloalkyl, 3-12 saturated or unsaturated heterocyclic group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, 6-10 aryl, 5-10 heteroaryl, oxo (=O).

[0269] "Heteroalkyl" refers to a straight-chain or branched, monovalent saturated aliphatic hydrocarbon group, wherein at least one carbon atom is replaced by one or more heteroatoms selected from O, N, S, S(=O), S(=O)2, or Si. The heteroatoms can appear in the middle or at the end of the group. "Heteroalkyl" also includes heteroalkylene groups, which are divalent groups of heteroalkyl groups, wherein the heteroatoms can occupy the middle or end of the chain, including but not limited to -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, and -CH2-CH2-N(CH3)-. CH3, -CH2-S-CH2-CH3, -O-CH2-CH2-O-CH3, -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-, the heteroalkyl or heteroalkylene groups described in this invention may optionally be substituted with the substituents described in this application.

[0270] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group that can combine with other groups. The "cycloalkyl" is monovalent or divalent, and the valence can be on the same atom or on two different atoms. The cycloalkyl also includes cycloalkenyl groups. Monocyclic cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, 3-8 membered cycloalkyl groups are used. More preferably, 3-6 membered cycloalkyl groups are used. Polycyclic cyclic hydrocarbon groups include cyclic, spirocyclic, fused-ring, or bridged-ring cyclic hydrocarbon groups, including, but not limited to, the following groups:

[0271] "Cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having at least one carbon-carbon double bond, but not forming a fully conjugated π-electron system, and capable of combining with other groups. Monocyclic cyclic alkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclohepttrienyl, cyclooctenyl, etc. Preferably, 3-8 membered cyclic alkenyl groups are preferred. More preferably, 3-6 membered cyclic alkenyl groups are preferred. More preferably, 5-6 membered cyclic alkenyl groups are preferred. Polycyclic cyclic alkenyl groups include linked, spirocyclic, fused, or bridged cyclic alkenyl groups. Including but not limited to the following groups:

[0272] The cycloalkyl or cycloalkenyl group can be fused with aryl, heteroaryl, or heterocyclic groups, including but not limited to tetrahydronaphthyl, benzocycloheptyl, etc.

[0273] "Alkenyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing one or more carbon-carbon double bonds. The "alkenyl" can be monovalent or divalent, and the valence can be on the same atom or on two different atoms. The alkenyl also includes alkenyl groups. Alkenyl groups include, but are not limited to, vinyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, and (Z)-but-1-enyl. Preferably, C... 2-6 Alkenyl. More preferably C 2- 4-Alkenyl.

[0274] "Heteroalkenyl" refers to an alkenyl group in which one or more heteroatoms selected from O, N, S, S(=O), S(=O)2, or Si are substituted for the carbon atom. These heteroatoms can appear in the middle or at the end of the group. The "heteroalkenyl" can be monovalent or divalent, and the valence can be on the same atom or on two different atoms. The heteroalkenyl also includes heteroalkenyl derivatives. Heteroalkenyl groups include, but are not limited to, -CH=CH-O-CH3, -CH=CH-NH-CH3, and -CH ＝ CH-N(CH3)-CH3, -CH2-S-CH=CH2.

[0275] "Heteroalkenyl" refers to a divalent group of heteroalkenyl, in which the heteroatom can occupy the middle or end 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-.

[0276] "Alynyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing one or more carbon-carbon triple bonds. The "alkynyl" group can be monovalent or divalent, and the valence can be on the same atom or on two different atoms. The alkynyl group also includes ynyleneyl groups. Alynyl groups include, but are not limited to, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, and but-3-alkynyl. Preferably, C... 2-6 Alkyne group. More preferably C 2-4 Alkyne group.

[0277] "alkylene" refers to a straight-chain or branched, divalent saturated aliphatic hydrocarbon group, in which one hydrogen atom of the alkyl group is further substituted. The two valences can be on the same atom or on two separate atoms. Examples include, but are not limited to, "methylene" which refers to -CH2- or =CH2, "ethylene" which refers to -CH2CH2-, =CHCH3, -CH(CH3)-, "propylene" which refers to -CH2CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH(CH3)CH2-, =CHCH2CH3, =C(CH3)2, and "butylene" which refers to -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, etc.

[0278] "Alkenyl" refers to a straight-chain or branched, divalent alkenyl group, in which one hydrogen atom of the alkenyl group is further substituted, including but not limited to "vinylene" which refers to -CH=CH-, "propenylene" which refers to -CH=CHCH2-, and "butenylene" which refers to -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=C(CH3)CH2-, etc.

[0279] "Idyne" refers to a straight-chain or branched, divalent alkynyl group, in which one hydrogen atom of the alkynyl group is further substituted, including but not limited to "ethynyl" which refers to -C≡C-, "propynyl" which refers to -C≡CCH2-, and "butynyl" which refers to -CH2C≡CCH2-, -C≡CCH2CH2-, etc.

[0280] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine and bromine.

[0281] "Halogenated alkyl" means an alkyl group as defined herein, in which one or more hydrogen atoms are substituted with the same or different halogens. This includes, but is not limited to, -CH2Cl, -CHF2, -CH2CCl3, -CH2CHF2, -CH2CF3, perfluoroalkyl (e.g., -CF3), etc.

[0282] "alkylamino" or "aminoalkyl" refers to NH3 that has been alkylated. This includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, etc.

[0283] "Dialkylamino" refers to a structure with N(C) 1-6 alkyl)2 or (C 1-6 Alkyl groups (2N) include, but are not limited to, dimethylamino, diethylamino, methyl(ethyl)amino, dipropylamino, diisopropylamino, etc.

[0284] "Aryl" refers to a monocyclic or polycyclic carbocyclic system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, and indenyl. The "aryl" group is monovalent or divalent. Preferably, it is a 6-10 member monocyclic or bicyclic aromatic group. More preferably, it is phenyl or naphthyl. Most preferably, it is phenyl.

[0285] A "heterocyclic group" refers to a non-aromatic monocyclic or polycyclic ring system having 1, 2, 3, 4, 5, or 6 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 fully conjugated π-electron system. The heteroatoms are independently selected from N, O, S, nitrogen oxides (NO), S(=O), S(O)(=NH), and S(=O)₂. The "heterocyclic group" is monovalent or divalent, and the valence can be on the same atom or on two different atoms. Polycyclic systems include fused rings, linked rings, bridged rings, or spirocyclic systems. Examples of monocyclic heterocyclic moiety include, but are not limited to: aziridine, aziridine, oxacyclobutane, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxopiperazinyl, oxopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolyl, isoxazolyl, thiazolinyl, isothiazolyl, quininecycloyl, thiadiazolyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc. Preferably, 4-7 membered heterocyclic moiety. More preferably, 4-6 membered heterocyclic moiety. Examples of polycyclic heterocyclic moiety 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-furan[3,4-b]pyrrole, hexahydro-1H-furan[3,4-c]pyrrole, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxa-2-azaspiro[3.4] Octyl, 6-oxa-2-azaspiro[3.4] Octyl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl and 1,4-dioxa-9-azaspiro[5.5]undec-9-yl, etc. Examples of unsaturated heterocyclic moieties include, but are not limited to:

[0286] The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl group, and the heterocyclic group is connected to the parent core structure, including but not limited to the following groups:

[0287] The heterocyclic group may be optionally substituted or unsubstituted, with the substituted group preferably being one or more of the following groups: deuterium atom, halogen, CN, nitro, hydroxyl, azido, C. 1-10Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 2-6 Heteroalkenyl, 3-12 saturated or unsaturated cycloalkyl, 3-12 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 aryl, 5-10 heteroaryl, oxo (=O).

[0288] "Heteroaryl" refers to a 5- to 14-membered mono- or polycyclic heteroaryl ring system, containing 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms independently selected from N, O, or S, with the remaining ring atoms being carbon atoms. The "heteroaryl" group is monovalent or divalent, and the valence can be on the same atom or on two different atoms. Examples of heteroaryl moieties include, but are not limited to: thiophene, thiazole, isothiazole, furan, imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiadiazole, oxadiazole, triazoles (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole), pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, indole, inzolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0289] The heteroaryl group can be fused to an aryl, heterocyclic, or cycloalkyl group, and the heteroaryl group is linked to the parent core structure, including but not limited to the following groups:

[0290] The heteroaryl group described in this invention may be optionally substituted with the substituent groups described in this application, preferably substituted with one or more of the following groups: deuterium atom, halogen, CN, nitro, hydroxyl, azide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Heteroalkenyl, 3-12 saturated or unsaturated cycloalkyl, 3-12 saturated or unsaturated heterocyclic group, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, 6-10 aryl, 5-10 heteroaryl, oxo (=O).

[0291] "Alkoxy" refers to a group having an -O-alkyl structure, wherein the alkoxy group is straight-chain or branched, including but not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, and other similar groups. C is preferred. 1-8 Alkyl group. More preferably, C1-6 Alkyl group. More preferably, C 1-4 Alkyl group.

[0292] "Cycloalkoxy" refers to -O-cycloalkyl, wherein the cycloalkyl group is as described above. Preferably C 3-8 Cycloalkoxy groups. Including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and other similar groups.

[0293] "Heterocyclic group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as described above. It includes, but is not limited to, azirrobutyloxy, oxacyclobutyloxy, pyrrolidinoxy, oxacyclohexyloxy, piperidinyloxy and other similar groups.

[0294] Any group defined above in this invention may be optionally replaced by a substituent group described in this application.

[0295] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt that adds to the compound of the present invention and possesses the pharmacological activity of the compound of the present invention, i.e., a conventional acid addition salt or base addition salt that retains the bioavailability and properties of the compound of the present invention, and is formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base. 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, carbonic acid, aminosulfonic 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, benzoic 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, hydroxyethylsulfonic 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, calcium, iron, aluminum, sodium, potassium, zinc, and magnesium salts. The organic bases include salts of primary, secondary, and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, and ethanolamine. Chemically modifying pharmaceutical compounds (i.e., drugs) into salts is a well-known technique among pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds.

[0296] "Prodrug molecule" refers to a prodrug that can be converted in vivo into the structure of the compound involved in this invention and its pharmaceutically acceptable salt.

[0297] "N-oxides" refer to compounds containing amine functional groups or heteroaryl compounds with N atoms, which can oxidize one or more N atoms to form N-oxides. + The compound is preferably an N-oxide of a tertiary amine or an N-oxide containing a heteroaryl group.

[0298] "Hydrate" refers to a compound formed with a certain amount of water.

[0299] "Solvate" refers to a complex formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, etc.

[0300] "Deuterated compounds" refer to compounds or groups formed when hydrogen atoms in the structure of a compound or chemical group are partially or completely replaced by the isotope deuterium. The "deuterated C" described in this invention... 1-6 "alkyl" refers to "C 1-6 "alkyl" refers to a group obtained by partially or completely replacing the hydrogen atoms in the alkyl structure with the isotope deuterium; "deuterated methyl" refers to a group obtained by partially or completely replacing the hydrogen atoms in the methyl structure with its isotope deuterium, preferably deuterated C. 1-3 Alkyl group, more preferably trideuterated methyl (CD3). The "deuterated C" of this invention 1-6 "Alkoxy" refers to "C 1-6 The term "alkoxy" refers to a group obtained by partially or completely replacing the hydrogen atom in the alkoxy structure with the isotope deuterium; "deuterated methoxy" refers to a group obtained by partially or completely replacing the hydrogen atom in the alkoxy structure with its isotope deuterium, preferably deuterated C. 1-3 Alkyl group, more preferably trideuterated methoxy (-OCD3).

[0301] "Isotope markers" are two or more atoms of the same chemical element with the same atomic number, occupying the same position on the periodic table, exhibiting almost identical chemical behavior, but differing in atomic mass or mass number.

[0302] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule. They can be divided into cis-trans isomers, enantiomers, and diastereomers.

[0303] Racemates include meso-racemates and exo-racemates.

[0304] "Tautomers" refer to structural isomers with different energies that undergo low-level interconversion. The compounds of this invention can exist as different tautomer forms, including but not limited to proton tautomers, which are interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0305] The compounds of the present invention may have one or more asymmetric centers, and such compounds may be individual stereoisomers (R or S) or mixtures thereof. The description or naming of specific compounds of the present invention also includes individual enantiomers, racemates, or other diastereomers.

[0306] "Patient" refers to an animal, preferably a mammal, and more preferably a human.

[0307] "Pharmaceutical composition" refers to the mixing of one or more of the compounds of this invention, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, with other chemical components, such as pharmaceutically acceptable carriers, excipients, or diluents. The purpose of a pharmaceutical composition is to facilitate administration to animals. Pharmaceutical compositions may include pharmaceutically acceptable excipients to mimic physiological conditions, such as pH adjusters and buffers, toxicity modifiers, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. Pharmaceutical compositions include, but are not limited to, the following forms: tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, sprays, sterile injectable solutions, or sterile packaged powders, etc.

[0308] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, component, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or potting material, which participates in loading or delivering the compound of the present invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that does not have excessive toxicity or side effects and is suitable for contact with animal tissues.

[0309] Some pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Sterile pyrogen-free water; (17) Physiological saline; (18) Ringer's solution; (19) Alcohols, such as ethanol and propanol; (20) Phosphate buffer; (21) Other substances that are non-toxic and compatible with the drug formulation, such as acetone.

[0310] Each pharmaceutically acceptable carrier should be compatible with other components, such as forming formulations with the compounds provided in this invention, and should not cause excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications to living biological tissues or organs, and should have a reasonable benefit-risk ratio.

[0311] Pharmaceutical ingredients can be formulated into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The methods and processes for preparing pharmaceutical compositions are well-known and can be carried out according to conventional processes, such as those described in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). Attached Figure Description

[0312] Figure 1 shows the tumor growth curves of a human lung cancer H1975 (EGFR L858R-T790M-C797S triple mutation) model mouse after administration of the test substance.

[0313] Figure 2 shows the relative body weight change (%) of mice in different groups; the relative body weight change was calculated based on the animals' body weight at the start of drug administration. Data points represent the percentage change in mean body weight within the group, and error bars represent standard errors (SEM). Detailed Implementation

[0314] Preparation of intermediates A1-A17 in the first group of preparation examples

[0315] Preparation of intermediate A1,5,7-dichloro-2-methyl-2H-pyrazolo[3,4-c]pyridine

[0316] Under nitrogen protection, 5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (500.0 mg, 2.66 mmol) was dissolved in THF (5 mL), cooled to 0 °C, and NaHMDS tetrahydrofuran solution (2 M, 2.0 mL, 3.99 mmol) was slowly added dropwise. The mixture was stirred at 0 °C for 0.5 h, and then iodomethane (1.1 g, 7.98 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed successively with water (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using ethyl acetate / petroleum ether (1 / 2) as the developing solvent to obtain 5,7-dichloro-2-methyl-2H-pyrazolo[3,4-c]pyridine (yellow oil, 310 mg, 57.7%). MS (ESI) + m / z = 202.1[M+H] + .

[0317] Preparation of intermediate A2. 2-(2-(benzyloxy)ethyl)-5,7-dichloro-2H-pyrazolo[3,4-c]pyridine

[0318] Under nitrogen protection, 5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (1.0 g, 5.32 mmol) was dissolved in DMF (30 mL), cesium carbonate (5.2 g, 15.96 mmol) was added, the mixture was cooled to 0 °C, and ((2-bromoethoxy)methyl)benzene (1.3 g, 5.85 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-100%) to obtain 2-(2-(benzyloxy)ethyl)-5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (yellow solid, 900 mg, 52.5%). MS(ESI + m / z = 322.0 [M+H] + .

[0319] Preparation of intermediate A3. 3-(5,7-dichloro-2H-pyrazolo[3,4-c]pyridin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0320] 3-(5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (2.0 g, 10.64 mmol) and tert-butyl 3-bromopyrrolidine-1-carboxylate were prepared using the method for synthesizing intermediate A2. MS (ESI) + m / z = 357.0 [M+H] + .

[0321] Preparation of intermediate A4. 5,7-dichloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-2H-pyrazolo[3,4-c]pyridine

[0322] 5,7-Dichloro-2H-pyrazolo[3,4-c]pyridine (4.0 g, 0.021 mol) was dissolved in DMF (80 mL), and cesium carbonate (10.4 g, 0.032 mol) and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (4.1 g, 0.021 mol) were added sequentially. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 2) as eluent to obtain 5,7-dichloro-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methyl)-2H-pyrazolo[3,4-c]pyridine (yellow solid, 1 g, 15.5%). MS (ESI) + m / z = 301.9[M+H] + .

[0323] Preparation of intermediate A5. 4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine

[0324] Under nitrogen protection, 4,6-dichloro-1H-imidazo[4,5-c]pyridine (2.0 g, 10.64 mmol) was dissolved in DMF (20 mL), cooled to 0 °C, and 60% NaH (553.2 mg, 13.83 mmol) was added. The mixture was stirred at 0 °C for 1 h, and then 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 2.3 g, 13.83 mmol) was added. The mixture was stirred for another 2 h. After the reaction was complete and the temperature was returned to room temperature, water (60 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (1 / 50-1 / 20) to obtain 4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine (yellow solid, 2 g, 59.0%). MS (ESI) + m / z = 318.0 [M+H] + .

[0325] Preparation of intermediate A6. 5,7-dichloro-2-((1-methylpiperidin-4-yl)methyl)-2H-pyrazolo[3,4-c]pyridine

[0326] Step 1: Under nitrogen protection, 5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (500.0 mg, 2.66 mmol) was dissolved in DMF (10 mL), and potassium carbonate (1.1 g, 7.98 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (813.8 mg, 2.93 mmol) were added sequentially. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (50 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using ethyl acetate / petroleum ether (1 / 3) as the developing solvent to obtain tert-butyl 4-((5,7-dichloro-2H-pyrazolo[3,4-c]pyridin-2-yl)methyl)piperidine-1-carboxylate (yellow oil, 440 mg, 42.6%). MS (ESI) + m / z = 385.2[M+H] + .

[0327] Step 2: Under nitrogen protection, tert-butyl 4-((5,7-dichloro-2H-pyrazolo[3,4-c]pyridin-2-yl)methyl)piperidine-1-carboxylate (500.0 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 5 mL, 19.47 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain 5,7-dichloro-2-(piperidine-4-ylmethyl)-2H-pyrazolo[3,4-c]pyridine (yellow solid, 400 mg, crude product). MS (ESI) + m / z = 285.1 [M+H] + .

[0328] Step 3: Under nitrogen protection, 5,7-dichloro-2-(piperidin-4-ylmethyl)-2H-pyrazolo[3,4-c]pyridine (80.0 mg, 0.28 mmol) was dissolved in methanol (4 mL), followed by the addition of acetic acid (1 mL) and an aqueous solution of formaldehyde (33.7 mg, 1.12 mmol). The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (35.3 mg, 0.56 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, water (50 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using methanol / dichloromethane (1 / 5) as the developing solvent to obtain 5,7-dichloro-2-((1-methylpiperidin-4-yl)methyl)-2H-pyrazolo[3,4-c]pyridine (yellow oil, 60 mg, 71.5%). MS (ESI) + m / z = 299.1 [M+H] + .

[0329] Preparation of intermediate A7. 5,7-dichloro-2-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-c]pyridine

[0330] Using 5,7-dichloro-2-(tetrahydro-2H-pyrazolo[3,4-c]pyridine (3.0 g, 15.96 mmol) and 4-bromotetrahydropyran (2.6 g, 15.96 mmol) as starting materials, 5,7-dichloro-2-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-c]pyridine was prepared according to the first step of the synthesis of intermediate A6. MS (ESI) + m / z = 272.1 [M+H] + .

[0331] Preparation of intermediate A8. 5,7-dichloro-2-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-c]pyridine

[0332] Under nitrogen protection, 5,7-dichloro-2H-pyrazolo[3,4-c]pyridine (100.0 mg, 0.53 mmol) was dissolved in toluene (3 mL), followed by the addition of 1-methylpiperidin-4-ol (61.3 mg, 0.53 mmol) and CMBP (154.0 mg, 0.64 mmol). The mixture was heated to 80 °C and stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography using methanol / dichloromethane (1 / 10) as the developing solvent to obtain 5,7-dichloro-2-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-c]pyridine (yellow oil, 30 mg, 19.5%). MS (ESI) + m / z = 285.1 [M+H] + .

[0333] Preparation of intermediate A9. 5,7-dichloro-2,3-dimethyl-2H-pyrazolo[3,4-c]pyridine

[0334] Step 1: Under nitrogen protection, 5,7-dichloro-2-methyl-2H-pyrazolo[3,4-c]pyridine (700.0 mg, 3.46 mmol) was dissolved in acetic acid (10.5 mL), and N-iodosuccinimide (1.6 g, 6.93 mmol) was added. The mixture was heated to 80 °C and stirred for 1 h. After the reaction was complete, it was cooled to room temperature, and saturated sodium thiosulfate solution (50 mL) was added to the reaction solution. The mixture was stirred for 10 min, filtered, and the residue was dried to obtain 5,7-dichloro-3-iodo-2-methyl-2H-pyrazolo[3,4-c]pyridine (intermediate A13, white solid, 630 mg, 55.5%). MS (ESI) + m / z = 328.0 [M+H] + .

[0335] Step 2: Under nitrogen protection, 5,7-dichloro-3-iodo-2-methyl-2H-pyrazolo[3,4-c]pyridine (590.0 mg, 1.80 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of methylboric acid (129.2 mg, 2.16 mmol), Pd(dppf)Cl2 (131.6 mg, 0.18 mmol), potassium carbonate (746.0 mg, 5.40 mmol), and water (0.5 mL). The mixture was then heated to 100 °C and stirred for 1 h. After the reaction was complete and cooled to room temperature, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-100%) to obtain 5,7-dichloro-2,3-dimethyl-2H-pyrazolo[3,4-c]pyridine (yellow solid, 250 mg, 64.3%). MS (ESI) + m / z = 216.0 [M+H] + .

[0336] Preparation of intermediate A10. 2-(2-(benzyloxy)ethyl)-5,7-dichloro-3-methyl-2H-pyrazolo[3,4-c]pyridine

[0337] Using 2-(2-(benzyloxy)ethyl)-5,7-dichloro-2H-pyrazolo[3,4-c]pyridine and NIS as starting materials, 2-(2-(benzyloxy)ethyl)-5,7-dichloro-3-methyl-2H-pyrazolo[3,4-c]pyridine was prepared according to the method for synthesizing intermediate A9. MS(ESI) + m / z = 336.0 [M+H] + .

[0338] Preparation of intermediate A11, 2,6-dichloro-N-methyl-3-nitropyridine-4-amine

[0339] Under nitrogen protection, 2,6-dichloro-3-nitropyridine-4-amine (25.0 g, 0.12 mol) was dissolved in acetonitrile (300 mL), cooled to 0 °C, and potassium carbonate (41.5 g, 0.30 mol) was added. The mixture was stirred at 0 °C for 0.5 h, and then iodomethane (51.2 g, 0.36 mol) was added. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and water (100 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (1 / 70-1 / 30) to obtain 2,6-dichloro-N-methyl-3-nitropyridine-4-amine (yellow solid, 11 g, 41.5%). MS(ESI + m / z = 222.0[M+H] + .

[0340] Preparation of intermediate A12.4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

[0341] 4,6-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (white solid, 2 g, 59.0%) was prepared from 4,6-dichloro-5-azaindole using the method for synthesizing intermediate A5. MS (ESI) + m / z = 317.1 [M+H] + .

[0342] Preparation of intermediate A14. 5,7-dichloro-1,3-dimethyl-1H-pyrazolo[3,4-c]pyridine

[0343] 5,7-Dichloro-1,3-Dimethyl-1H-pyrazolo[3,4-c]pyridine (yellow solid, 350 mg, 22.9%) was prepared from 5,7-dichloro-3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridine and methylboronic acid according to the second step of the synthesis of intermediate A9. MS (ESI) + m / z = 215.9 [M+H] + .

[0344] Intermediate A15. 1,3-Dichloro-6,7-dihydropyridine[3',4:4,5]imidazo[1,2-a]pyrazine-8(9H)-benzyl formate.

[0345] Step 1: 2,4,6-Trichloro-3-nitropyridine (50 g, 0.22 mol) was dissolved in DMF (500 mL), and 2-(tert-butyldimethylsiloxy)ethylamine (42.4 g, 0.24 mol) and triethylamine (22.2 g, 0.22 mol) were added sequentially. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-20 / 1) to obtain N-(2-(tert-butyldimethylsiloxy)ethyl)-2,6-dichloro-3-nitropyridine-4-amine (yellow oil, 42 g, 52.1%). MS (ESI) + m / z = 367.1 [M+H] + .

[0346] Step 2: N-(2-(tert-butyldimethylsiloxy)ethyl)-2,6-dichloro-3-nitropyridine-4-amine (42 g, 0.11 mol) was dissolved in a mixture of ethanol and water (v / v = 5 / 1, 420 mL), and ammonium chloride (24.5 g, 0.45 mol) and iron powder (25.6 g, 0.45 mol) were added. The mixture was heated to 50 °C and stirred for 4 h. After the reaction was complete, it was cooled to room temperature, filtered, and the residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-1 / 1) to obtain N 4 2-(2-(tert-butyldimethylsiloxy)ethyl)-2,6-dichloropyridine-3,4-diamine (brown solid, 25 g, 64.8%). MS (ESI) + m / z = 336.2[M+H] + .

[0347] Step 3: Transfer N 4-(2-(tert-butyldimethylsiloxy)ethyl)-2,6-dichloropyridine-3,4-diamine (25 g, 74.3 mmol) was dissolved in DMF (250 mL), and N-benzyloxycarbonyl-glycine (23.3 g, 111.5 mmol), triethylamine (15 g, 148.7 mmol), HATU (42.4 g, 111.5 mmol) and DMAP (0.91 g, 7.43 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (10 / 1-2 / 1) to obtain benzyl(2-((4-(((2-tert-butyldimethylsiloxy)ethyl)amino)-2,6-dichloropyridin-3-yl)amino)-2-oxoethyl)carbamate (yellow oil, 20 g, 51%). MS (ESI) + m / z = 529.2 [M+H] + .

[0348] Step 4: Under nitrogen protection, benzyl(2-((4-((2-tert-butyldimethylsiloxy)ethyl)amino)-2,6-dichloropyridin-3-yl)amino)-2-oxoethyl)carbamate (17g, 32.2mmol) was dissolved in 1,4-dioxane (170mL), sodium hydroxide (1.93g, 48.3mmol) was added, and the mixture was heated to 50℃ and stirred for 2h. After the reaction was complete and cooled to room temperature, water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-10 / 1) to obtain ((1-(2-(tert-butyldimethylsiloxy)ethyl)-4,6-dichloro-1H-imidazo[4,5-c]pyridin-2-yl)methyl)carbamate (yellow solid, 10 g, 61%). MS (ESI) + m / z = 509.1 [M+H] + .

[0349] Step 5: Under nitrogen protection, 10 g (19.6 mmol) of ((1-(2-(tert-butyldimethylsiloxy)ethyl)-4,6-dichloro-1H-imidazo[4,5-c]pyridin-2-yl)methyl)carbamate was dissolved in tetrahydrofuran (100 mL), and 29.4 mL (29.4 mmol) of 1 M TBAF tetrahydrofuran solution was added. The mixture was heated to 50 °C and stirred for 3 h. After the reaction was complete and cooled to room temperature, water (300 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (10 / 1-1 / 2) to obtain benzyl (4,6-dichloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]pyridin-2-yl)methyl)carbamate (yellow solid, 6 g, 77.2%). MS (ESI) + m / z = 395.0 [M+H] + .

[0350] Step 6: Under nitrogen protection, (4,6-dichloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]pyridin-2-yl)methyl)benzyl carbamate (4.3 g, 10.88 mmol) was dissolved in toluene (45 mL), and CMBP (13.1 g, 54.5 mmol) was added. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was first separated by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (1 / 0-2 / 1) to obtain the crude product. The crude product was then slurried with methanol (10 mL), filtered, and the residue was dried to obtain 3-dichloro-6,7-dihydropyridine[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carbamate (yellow solid, 1.9 g, 46.3%). MS (ESI) + m / z = 377.1 [M+H] + .

[0351] Preparation of intermediate A16. 6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxaldehyde

[0352] Step 1: Under nitrogen protection, methyl 6-chloro-2H-pyrazolo[4,3-c]pyridine-3-carboxylate (2.5 g, 11.79 mmol) was dissolved in DMF (30 mL), and potassium carbonate (3.25 g, 23.58 mmol) and methyl iodomethane (2.0 g, 14.15 mmol) were added. The mixture was stirred at room temperature for 0.5 h. After the reaction was complete, saturated brine (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (4 / 1-3 / 1) to obtain methyl 6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylate (off-white solid, 0.8 g, 30%). MS (ESI) + m / z = 226.0 [M+H] + .

[0353] Step 2: Under nitrogen protection, morpholine (1.1 g, 12.69 mmol) was dissolved in tetrahydrofuran (4 mL). At 0 °C, this solution was added dropwise to a hexane solution of DIBAL-H (1 M, 12.3 mL, 12.3 mmol). The mixture was stirred at 0 °C for 5 min. Then, this mixture was added dropwise to a tetrahydrofuran solution of methyl 6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxylate (0.7 g, 3.09 mmol). The mixture was heated to room temperature and stirred for 2 h. After the reaction was complete, water (10 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (3 / 1-2 / 1) to obtain 6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine-3-carboxaldehyde (white solid, 0.5 g, 86%). MS (ESI) + m / z = 196.1 [M+H] + .

[0354] Preparation of intermediate A17. 4,6-dichloro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole[4,3-c]pyridine

[0355] 4,6-Dichloro-1H-pyrazolo[4,3-c]pyridine (white solid, 1.2 g, 71.5%) was prepared from 4,6-dichloro-1H-pyrazolo[4,3-c]pyridine using the method for synthesizing intermediate A5. MS (ESI) + m / z = 318.0 [M+H]+ .

[0356] Preparation of intermediates B1-B14 in the second group of preparation examples

[0357] Preparation of intermediate B1.(S)-4-(tert-butyldimethylsiloxy)-N-methylbut-2-amine

[0358] Step 1: Under nitrogen protection, (R)-1,3-butanediol (5.0 g, 0.055 mol) was dissolved in dichloromethane (50 mL), cooled to 0 °C, and imidazole (7.6 g, 0.11 mol) was added. Then, tert-butyldimethylchlorosilane (10.9 g, 0.072 mol) was added in portions, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, ice water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-4-(tert-butyldimethylsiloxy)but-2-ol (pale yellow oil, 8 g, 70.8%). MS (ESI) + m / z = 205.2[M+H] + .

[0359] Step 2: Under nitrogen protection, (R)-4-(tert-butyldimethylsiloxy)but-2-ol (8.0 g, 0.039 mol) was dissolved in pyridine (80 mL), cooled to 0 °C, and 4-dimethylaminopyridine (1.0 g, 7.82 mmol) was added. Then, p-toluenesulfonyl chloride (11.2 g, 0.059 mol) was added in portions, and the mixture was stirred overnight at room temperature. After the reaction was complete, water (250 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3) as the eluent to obtain (R)-4-(tert-butyldimethylsiloxy)but-2-p-methylbenzenesulfonate (yellow oil, 6 g, 42.7%).

[0360] Step 3: (R)-4-(tert-butyldimethylsiloxy)but-2-p-methylbenzenesulfonate (10.0 g, 27.89 mmol) was dissolved in ethanol (100 mL), sodium carbonate (5.9 g, 55.78 mmol) was added, the mixture was cooled to 0 °C, and 30% methylamine ethanol solution (8.7 g, 83.67 mmol) was added. The mixture was heated to 60 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-4-(tert-butyldimethylsiloxy)-N-methylbut-2-amine (yellow oil, 332 mg, 55.1%). MS (ESI) + m / z = 218.2[M+H] + .

[0361] Preparation of intermediate B2.(R)-4-(tert-butyldimethylsiloxy)-N-methylbut-2-amine

[0362] (R)-4-(tert-butyldimethylsiloxy)-N-methylbut-2-amine (yellow oil, 4 g, 66.1%) was prepared from (S)-1,3-butanediol (20.0 g, 0.22 mol) and tert-butyldimethylchlorosilane (40.1 g, 0.27 mol) according to the method for synthesizing intermediate B1. MS (ESI) + m / z = 218.2[M+H] + .

[0363] Preparation of intermediate B3, 3-(tert-butyldimethylsiloxy)-N,2-dimethylpropyl-1-amine

[0364] 3-(tert-butyldimethylsiloxy)-N,2-dimethylpropane-1-amine (pale yellow oil, 6.4 g, crude product) was prepared from 2-methyl-1,3-propanediol (15.0 g, 0.17 mol) using the method for synthesizing intermediate B1. MS (ESI) + m / z = 218.2[M+H] + .

[0365] Preparation of intermediate B4, 3-(tert-butyldimethylsiloxy)-N-methylpropyl-1-amine

[0366] 3-(tert-butyldimethylsiloxy)-N-methylprop-1-amine was prepared from 3-(methylamino)prop-1-ol (10.0 g, 0.11 mol) according to the first step of the synthesis of intermediate B1.

[0367] 1 H NMR (400MHz, CDCl3) δ3.60(t,J=6.4Hz,2H),3.43(br s,1H),2.51-2.48(m,2H),2.25(s,3H),1.59-1.54(m,2H),0.84(s,9H),0.00(s,6H).

[0368] Preparation of intermediate B5.(S)-5-(tert-butyldimethylsiloxy)-N-methylpentane-2-amine

[0369] Step 1: Under nitrogen protection, (S)-5-oxotetrahydrofuran-2-carboxylic acid (45.0 g, 0.35 mol) was dissolved in tetrahydrofuran (500 mL), cooled to 0 °C, and a dimethyl sulfide solution of borane (10 M, 35 mL, 0.35 mol) was added. The mixture was then heated to room temperature and stirred for 3 h. After the reaction was complete, the temperature was lowered to 0 °C, and methanol (500 mL) was added to the reaction solution. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (1 / 10-1 / 1) to obtain (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (yellow oil, 20 g, 50.1%).

[0370] Step 2: Dissolve (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (32.0 g, 0.28 mol) in dichloromethane (400 mL), add 4-dimethylaminopyridine (3.4 g, 0.028 mol) and triethylamine (55.8 g, 0.55 mol) in sequence, cool to 0 °C, add p-toluenesulfonyl chloride (57.8 g, 0.30 mol) in portions, heat to room temperature and stir for 6 h. After the reaction was complete, water (200 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (1 / 20-1 / 1) to obtain (S)-p-toluenesulfonic acid-(5-oxotetrahydrofuran-2-yl)methyl ester (yellow solid, 65 g, 87.3%). MS (ESI) + m / z = 271.2[M+H] + .

[0371] Step 3: Dissolve (S)-p-toluenesulfonic acid-(5-oxotetrahydrofuran-2-yl)methyl ester (50.0 g, 0.18 mol) in tetrahydrofuran (500 mL), cool to 0 °C, add lithium aluminum hydride (28.1 g, 0.74 mol), heat to 70 °C and stir for 16 h. After the reaction is complete, cool to room temperature, add sodium sulfate decahydrate to the reaction solution, filter, wash the filter residue with dichloromethane, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using methanol / dichloromethane (1 / 20) as eluent to obtain (R)-pentane-1,4-diol (yellow oil, 11.5 g, 59.8%).

[0372] Steps 4 to 6: Using (R)-pentane-1,4-diol (12.0 g, 0.12 mol) and TBSCl (17.4 g, 0.12 mol) as raw materials, (S)-5-(tert-butyldimethylsiloxy)-N-methylpentane-2-amine (yellow oil, 6 g, crude product) was prepared according to the method for synthesizing intermediate B1. MS (ESI) + m / z = 232.4[M+H] + .

[0373] Preparation of intermediate B6.(S)-3-(benzyloxy)-N,2-dimethylpropyl-1-amine

[0374] Step 1: Methyl (R)-3-hydroxy-2-methylpropionate (24.5 g, 0.21 mol) was dissolved in THF (122.5 mL), cooled to 0 °C, and trichloroacetylimine benzyl ester (57.6 g, 0.23 mol) and trifluoromethanesulfonic acid (9.3 g, 0.062 mol) were added dropwise. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was allowed to return to room temperature, and water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (500 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl (R)-3-(benzyloxy)-2-methylpropionate (colorless oil, 20 g, 46.3%).

[0375] Step 2: Methyl (R)-3-(benzyloxy)-2-methylpropionate (15.0 g, 0.072 mol) was dissolved in THF (150 mL), cooled to 0 °C, and a THF solution of lithium aluminum hydride (1 M, 5.5 g, 0.14 mol) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, water (6 mL) was added dropwise at 0 °C, followed by NaOH solution (1 M, 6 mL) and water (18 mL). The mixture was stirred for 30 min, filtered, and water (200 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-3-(benzyloxy)-2-methylprop-1-ol (colorless oil, 12 g, 92.4%).

[0376] Steps 3 and 4: Using (S)-3-(benzyloxy)-2-methylprop-1-ol (12.0 g, 66.62 mmol), (S)-3-(benzyloxy)-N,2-dimethylprop-1-amine was prepared following steps 2 and 3 of the synthesis of intermediate B1. MS (ESI) + m / z = 194.3 [M+H] + .

[0377] Preparation of intermediate B7.(S)-4-(tert-butyldimethylsiloxy)-N,3,3-trimethylbut-2-amine

[0378] Step 1: Dissolve methyl 2,2-dimethyl-3-oxobutyrate (15.0 g, 0.10 mol) in a mixture of 1,4-dioxane and water (300 mL), then add (S)-1-phenylethylamine (12.6 g, 0.10 mol), acetic acid (3.1 g, 0.052 mol), and sodium cyanoborohydride (13.1 g, 0.21 mol) in sequence, and heat to 60 °C and stir overnight. After the reaction was complete and cooled to room temperature, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with sodium bicarbonate aqueous solution (50 mL × 2), and extracted with hydrochloric acid aqueous solution (1 M, 150 mL × 3). The aqueous phase was collected, and the pH was adjusted to 8 with saturated sodium carbonate solution, followed by extraction with ethyl acetate (200 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl (S)-2,2-dimethyl-3-(((S)-1-phenylethyl)amino)butyrate (white solid, 11.1 g, 42.8%). MS (ESI) + m / z = 250.2[M+H] + .

[0379] Step 2: Dissolve methyl (S)-2,2-dimethyl-3-(((S)-1-phenylethyl)amino)butyrate (30.0 g, 0.12 mol) in methanol (100 mL), then add formaldehyde aqueous solution (28.9 g, 0.96 mol) and acetic acid (10.8 g, 0.18 mol) in sequence, stir at room temperature for 0.5 h, then add sodium cyanoborohydride (30.2 g, 0.48 mol) in portions, and stir at room temperature overnight. After the reaction was complete, the temperature was lowered to 0℃, and saturated sodium bicarbonate solution (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (500 mL × 2), the organic phases were combined and washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (0-3 / 50) to obtain methyl (S)-2,2-dimethyl-3-(methyl((S)-1-phenylethyl)amino)butyrate (white solid, 5 g, 15.8%). MS (ESI) + m / z = 264.2[M+H] + .

[0380] Step 3: Methyl (S)-2,2-dimethyl-3-(methyl((S)-1-phenylethyl)amino)butyrate (5.0 g, 18.98 mmol) was dissolved in THF (50 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (1 M, 38 mL, 37.97 mmol) was added. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, water (300 mL) was added to the reaction solution, followed by anhydrous sodium sulfate (6 g) and stirring for 0.5 h. The mixture was filtered, and the residue was washed with tetrahydrofuran (100 mL × 2). The filtrate was concentrated under reduced pressure to obtain (S)-2,2-dimethyl-3-(methyl((S)-1-phenylethyl)amino)but-1-ol (4.7 g, crude product). MS (ESI) + m / z = 236.2[M+H] + .

[0381] Step 4: Using (S)-2,2-dimethyl-3-(methyl((S)-1-phenylethyl)amino)but-1-ol (4.7 g, 19.98 mmol) as a starting material, (S)-4-(tert-butyldimethylsiloxy)-N,3,3-trimethyl-N-((S)-1-phenylethyl)but-2-amine (white solid, 4.8 g, 68.8%) was prepared following the method described in Step 1 of the synthesis of intermediate B1. MS (ESI) + m / z = 350.3[M+H] + .

[0382] Step 5: Under nitrogen protection, (S)-4-(tert-butyldimethylsiloxy)-N,3,3-trimethyl-N-((S)-1-phenylethyl)but-2-amine (4.8 g, 13.73 mmol) was dissolved in methanol (100 mL), and palladium hydroxide on carbon (2.5 g, 17.85 mmol) was added to displace hydrogen. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was filtered, and the residue was washed with ethyl acetate (100 mL × 2). The filtrate was concentrated under reduced pressure to obtain (S)-4-(tert-butyldimethylsiloxy)-N,3,3-trimethylbut-2-amine (white solid, 3 g, 89.0%). MS (ESI) + m / z = 246.2[M+H] + .

[0383] Preparation of intermediate B8. 3-(tert-butyldimethylsiloxy)-N,2,2-trimethylpropyl-1-amine

[0384] Step 1: Using 3-amino-2,2-dimethylprop-1-ol (10.5 g, 0.10 mol) as the starting material, 3-(tert-butyldimethylsiloxy)-2,2-dimethylprop-1-amine (white solid, 26.2 g, crude product) was prepared according to the method in Step 1 of the synthesis of intermediate B1. MS (ESI) + m / z = 218.2[M+H] + .

[0385] Step 2: Dissolve 3-(tert-butyldimethylsiloxy)-2,2-dimethylpropyl-1-amine (26.0 g, 0.12 mol) in DCM (400 mL), then add triethylamine (24.2 g, 0.24 mol) and benzooxycarbonyl succinimide (35.8 g, 0.14 mol) sequentially, and stir overnight at room temperature. After the reaction is complete, add water (150 mL) to the reaction solution, extract the mixture with dichloromethane (200 mL × 3), combine the organic phases, dry them with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-1 / 10) to obtain (3-(tert-butyldimethylsiloxy)-2,2-dimethylpropyl)carbamate (colorless oil, 10 g, 23.8%). MS (ESI) + m / z = 352.2[M+H] + .

[0386] Step 3: Dissolve (10.0 g, 28.44 mmol) of (3-(tert-butyldimethylsiloxy)-2,2-dimethylpropyl)carbamate in DMF (90 mL), cool to 0 °C, add 60% NaH (2.5 g, 62.58 mmol), and heat to room temperature while stirring for 0.5 h. Then cool to 0 °C, add a DMF (10 mL) solution of methyl iodide (5.4 g, 38.05 mmol), and heat to room temperature while stirring for 2 h. After the reaction was complete, water (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (80 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-1 / 5) to obtain (3-(tert-butyldimethylsiloxy)-2,2-dimethylpropyl)(methyl)carbamate (yellow oil, 9 g, 86.6%). MS (ESI) + m / z = 366.3 [M+H] + .

[0387] Step 4: Under nitrogen protection, (3-(tert-butyldimethylsiloxy)-2,2-dimethylpropyl(methyl)carbamate (9.0 g, 24.62 mmol) was dissolved in ethyl acetate (90 mL), and 10% Pd / C (3.9 g, 3.69 mmol) was added to replace the hydrogen atmosphere. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was filtered through diatomaceous earth. The residue was washed with ethyl acetate (50 mL × 3), and the filtrate was concentrated under reduced pressure to give 3-(tert-butyldimethylsiloxy)-N,2,2-trimethylpropyl-1-amine (pale yellow oil, 5.4 g, crude product). MS (ESI) + m / z = 232.3[M+H] + .

[0388] Preparation of intermediate B9. 1-(tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-N-methylmethylamine

[0389] 1-(tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-N-methylmethylamine was prepared from (1-(aminomethyl)cyclopropyl)methanol using the method for synthesizing intermediate B8. MS(ESI) + m / z = 230.2[M+H] + .

[0390] Preparation of intermediate B10. 1-(2-(tert-butyldimethylsiloxy)ethyl)-N-methylcycloprop-1-amine

[0391] Steps 1 and 2: Using (1-(2-hydroxyethyl)cyclopropyl)carbamate tert-butyl ester (9.95 g, 49.44 mmol) as the starting material, (1-(2-(tert-butyldimethylsiloxy)ethyl)cyclopropyl)(methyl)carbamate tert-butyl ester (colorless oil, 16 g, 77.2%) was prepared according to the methods in steps 1 and 3 of the synthesis of intermediate B8, respectively. MS (ESI) + m / z = 330.3[M+H] + .

[0392] Step 3: Dissolve tert-butyl (1-(2-(tert-butyldimethylsiloxy)ethyl)cyclopropyl)(methyl)carbamate (8.0 g, 24.28 mmol) in DCM (150 mL), add 2,6-dimethylpyridine (3.9 g, 36.41 mmol), cool to 0 °C, add a DCM solution of trimethylsilyltrifluoromethanesulfonate (8.1 g, 36.41 mmol) (10 mL), and heat to room temperature with stirring for 3 h. After the reaction is complete, add dichloromethane (100 mL) and water (100 mL) to the reaction solution, collect the organic phase, extract the aqueous phase with dichloromethane (200 mL × 2), combine the organic phases and wash with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 1-(2-(tert-butyldimethylsiloxy)ethyl)-N-methylcyclopropyl-1-amine (yellow solid, 6.3 g, crude product). MS(ESI + m / z = 230.2[M+H] + .

[0393] Preparation of intermediate B11.4-(tert-butyldiphenylsiloxy)-1,1,1-trifluoro-N-methylbut-2-amine

[0394] Step 1: Ethyl 3-amino-4,4,4-trifluorobutyrate (16.8 g, 98.2 mmol) was dissolved in methanol (300 mL), cooled to 0 °C, and triethylamine (28.8 g, 284.6 mmol) and di-tert-butyl dicarbonate (62.22 g, 285.1 mmol) were added sequentially. The mixture was stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (0-1 / 10) to obtain ethyl 3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyrate (colorless oil, 11 g, 37.3%). MS (ESI) + m / z = 286.2[M+H] + .

[0395] Step 2: Using ethyl 3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyrate (10.0 g, 35.06 mmol) as the starting material, tert-butyl (1,1,1-trifluoro-4-hydroxybutane-2-yl)carbamate (colorless oil, 6.5 g, 76.2%) was prepared according to the method described in Step 2 of the synthesis of intermediate B6. MS (ESI) + m / z = 244.7[M+H] + .

[0396] Steps 3, 4, and 5: Using (1,1,1-trifluoro-4-hydroxybutane-2-yl)carbamate tert-butyl ester (6.5 g, 26.72 mmol) and tert-butyldiphenylchlorosilane (9.9 g, 36.08 mmol) as starting materials, 4-(tert-butyldiphenylsiloxy)-1,1,1-trifluoro-N-methylbut-2-amine (yellow solid, 6.7 g, 63.4%) was prepared according to the method for synthesizing intermediate B10. MS (ESI) + m / z = 396.2[M+H] + .

[0397] Preparation of intermediate B12.(S)-4-(tert-butyldimethylsiloxy)but-2-ol

[0398] (S)-4-(tert-butyldimethylsiloxy)but-2-ol (colorless oil, 9.2 g, 81.1%) was prepared from (S)-1,3-butanediol (5.0 g, 55.48 mmol) following the first step of the synthesis of intermediate B1. MS (ESI) + m / z = 205.2[M+H] + .

[0399] Preparation of intermediate B13, 4-(tert-butyldimethylsiloxy)-N-methylpentane-1-amine

[0400] 4-(tert-butyldimethylsiloxy)-N-methylpentane-1-amine (colorless oil, 3.0 g, 96.6%) was prepared from 1,4-pentanediol using the first, third, second, and fourth steps of the synthesis of intermediate B1. MS (ESI) + m / z = 232.2[M+H] + .

[0401] Preparation of intermediate B14, 2-(3-(tert-butyldimethylsiloxy)propyl)pyrrolidine

[0402] Step 1: Under nitrogen protection, dimethyl sulfoxide (4.98 g, 63.75 mmol) was dissolved in dichloromethane (100 mL), cooled to -78 °C, and oxaloyl chloride (5.39 g, 42.5 mmol) was slowly added. The mixture was stirred at -78 °C for 1 h, followed by the addition of 2-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (5 g, 21.25 mmol). The mixture was stirred at -78 °C for another 4 h, and then N,N-diisopropylethylamine (13.73 g, 106.25 mmol) was slowly added. The mixture was heated to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-5 / 1) to obtain benzyl 2-formylpyrrolidine-1-carboxylate (yellow oil, 2 g, 40.3%). MS (ESI) + m / z = 234.1 [M+H] + .

[0403] Step 2: Under nitrogen protection, 2-formylpyrrolidine-1-carboxylic acid benzyl ester (2 g, 8.57 mmol) was dissolved in dichloromethane (50 mL), and methyl 2-(triphenyl-phosphine)acetate (2.87 g, 8.57 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-5 / 1) to obtain (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid benzyl ester (yellow oil, 1.5 g, 60.5%). MS (ESI) + m / z = 290.1 ​​[M+H] + .

[0404] Step 3: (E)-2-(3-methoxy-3-oxopropyl-1-en-1-yl)pyrrolidine-1-carboxylate benzyl ester (500 mg, 1.72 mmol) was dissolved in tetrahydrofuran (10 mL), and triethyllithium borohydride (1 M, 5.2 mL, 5.18 mmol) was added. The mixture was cooled to 0 °C and stirred for 2 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (E)-2-(3-hydroxypropyl-1-en-1-yl)pyrrolidine-1-carboxylate benzyl ester (yellow oil, 400 mg, 88.6%). MS (ESI) + m / z = 262.2[M+H] + .

[0405] Step 4: Using (E)-2-(3-hydroxyprop-1-en-1-yl)pyrrolidine-1-carboxylate as the starting material, (E)-2-(3-(tert-butyldimethylsiloxy)prop-1-en-1-yl)pyrrolidine-1-carboxylate (yellow oil, 450 mg, 78.3%) was prepared according to the method in Step 1 of the synthesis of intermediate B1. MS (ESI) + m / z = 376.3 [M+H] + .

[0406] Step 5: Under nitrogen protection, (E)-2-(3-(tert-butyldimethylsiloxy)prop-1-en-1-yl)pyrrolidine-1-carboxylic acid benzyl ester (400 mg, 1.07 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (56.4 mg, 0.05 mmol) was added to replace the hydrogen gas. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-(3-(tert-butyldimethylsiloxy)propyl)pyrrolidine (yellow oil, 250 mg, 96.4%). MS (ESI) + m / z = 244.2[M+H] + .

[0407] Preparation of intermediates C1-C54 in the third group of preparation examples

[0408] Preparation of intermediate C1.(S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N,1-dimethyl-1H-imidazo[4,5-c]pyridine-4-amine

[0409] Intermediate B1 (500.0 mg, 2.30 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of potassium tert-butoxide (1.0 g, 9.20 mmol) and 4,6-dichloro-1-methyl-1H-imidazo[4,5-c]pyridine (464.6 mg, 2.30 mmol). The mixture was heated to 70 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and ice water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed with saturated brine (15 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N,1-dimethyl-1H-imidazo[4,5-c]pyridine-4-amine (yellow oil, 300 mg, 34.1%). MS (ESI) + m / z = 383.1 [M+H] + .

[0410] Preparation of intermediates C2-C18.

[0411] Intermediates C2-C18 were prepared using intermediates A6, A8, A11, B1-B4, B6-B14, or commercially available N-methylamino alcohols as raw materials, following the method used to synthesize intermediate C1. The base used was triethylamine, NaH, or DIEA; the solvent was dichloromethane or isopropanol; and the reaction temperature was 0°C to reflux. See Table 1 for details.

[0412] Table 1. Raw materials, structure, and characterization data of intermediates C2-C18

[0413] Preparation of intermediate C19.(S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-5-chloro-N,2-dimethyl-2H-pyrazolo[3,4-c]pyridine-7-amine

[0414] Intermediate A1 (300.0 mg, 1.48 mmol) was dissolved in NMP (3 mL), followed by the addition of DIEA (1.5 g, 11.88 mmol) and intermediate B1 (387.4 mg, 1.78 mmol). The mixture was microwaved to 150 °C and stirred for 3 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 (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using ethyl acetate / petroleum ether (1 / 2) as the developing solvent to obtain (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-5-chloro-N,2-dimethyl-2H-pyrazolo[3,4-c]pyridine-7-amine (yellow solid, 300 mg, 52.7%). MS (ESI) + m / z = 383.2[M+H] + .

[0415] Preparation of intermediates C20-C35.

[0416] Intermediates C20-C35 were prepared from intermediates A2-A5, A7, A9-A14, A17 and B1, B5 or dichloroheroaryl compounds, following the method used to synthesize intermediate C19. The reaction temperature was 150℃ to 190℃. See Table 2 for details.

[0417] Table 2. Raw materials, structure, and characterization data of intermediates C20-C35

[0418] Preparation of intermediate C39.(S)-3-((5-chloro-2-methyl-3-(3-(methylsulfonyl)methyl)azacyclobutane-1-yl)-2H-pyrazolo[3,4-c]pyridin-7-yl)(methyl)amino)but-1-ol

[0419] (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-5-chloro-3-iodo-N,2-dimethyl-2H-pyrazolo[3,4-c]pyridine-7-amine (intermediate C32, 300 mg, 0.59 mmol) was dissolved in toluene (5 mL), and 3-(methylsulfonyl)methyl)azacyclobutane hydrochloride (131.10 g, 0.71 mmol), Sphos (31.3 g, 0.06 mmol), Sphos Pd G4 (46.06 g, 0.06 mmol), and cesium carbonate (577.56 mg, 1.77 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 12 h. After the reaction was complete and cooled to room temperature, water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (20 / 1-10 / 1) to obtain (S)-3-((5-chloro-2-methyl-3-(3-(methylsulfonyl)methyl)azacyclobutan-1-yl)-2H-pyrazolo[3,4-c]pyridin-7-yl)(methyl)amino)but-1-ol (yellow solid, 150 mg, 72.89%). MS (ESI) + m / z = 416.2[M+H] + .

[0420] Preparation of intermediate C40.(S)-1-((5-(tert-butyldimethylsiloxy)pent-2-yl)(methyl)amino)-3-chloro-6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-benzyl formate

[0421] Under nitrogen protection, intermediates A15 (900 mg, 2.39 mmol) and B5 (5.52 g, 23.86 mmol) were added to a microwave tube, and the mixture was heated to 130 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with dichloromethane (30 mL), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using petroleum ether / ethyl acetate (3 / 1) as the developing solvent to obtain ((S)-1-((5-(tert-butyldimethylsiloxy)pent-2-yl)(methyl)amino)-3-chloro-6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid benzyl ester (yellow solid, 200 mg, 14.6%). MS (ESI) + m / z = 572.3 [M+H] + .

[0422] Preparation of intermediate C43.(S)-3-((6-chloro-1-methyl-2-(methylamino)-1H-imidazo[4,5-c]pyridin-4-yl)(methyl)amino)but-1-ol

[0423] Step 1: Using (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 2 N 4 Using dimethylpyridine-2,3,4-triamine (C44-int 2) as a starting material, (S)-3-((3-amino-6-chloro-4-(methylamino)pyridin-2-yl)(methyl)amino)but-1-ol (C43-int 2, yellow solid, 632 mg) was prepared according to step 5 of the synthesis intermediate A15. MS (ESI) + m / z = 373.2[M+H] + .

[0424] Step 2: Dissolve (S)-3-((3-amino-6-chloro-4-(methylamino)pyridin-2-yl)(methyl)amino)but-1-ol (632 mg, 2.4 mmol) in 1,4-dioxane (10 mL), add methyl isothiocyanate (892 mg, 12.2 mmol), and heat to 90 °C with stirring for 5 h. After the reaction is complete, cool to room temperature, concentrate the reaction solution under reduced pressure, dilute the residue with water (10 mL), extract the mixture with ethyl acetate (20 mL × 3), combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using petroleum ether / ethyl acetate (5 / 1) as eluent to obtain (S)-1-(6-chloro-2-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)pyridin-3-yl)-3-methylthiourea (yellow solid, 535 mg, 66.0%). MS(ESI + m / z = 332.1[M+H] + .

[0425] Step 3: Dissolve (S)-1-(6-chloro-2-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)pyridin-3-yl)-3-methylthiourea (535 mg, 1.6 mmol) in 1,4-dioxane (5 mL), add EDCI (927 mg, 4.83 mmol), heat to 100 °C and stir overnight. After the reaction was complete and cooled to room temperature, the reaction solution was concentrated under reduced pressure. The residue was diluted with water (15 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 1) as eluent to obtain (S)-3-((6-chloro-1-methyl-2-(methylamino)-1H-imidazo[4,5-c]pyridin-4-yl)(methyl)amino)but-1-ol (yellow solid, 250 mg, 80.9%). MS (ESI) + m / z = 298.1 [M+H] + .

[0426] Preparation of intermediate C44.(S)-2-(4-((4-tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)prop-2-ol

[0427] Step 1: Using intermediate C4 as a raw material, prepare (S)-N according to the method in step 2 of the synthesis of intermediate A15. 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 2 N 42,3,4-Dimethylpyridine-2,3,4-triamine (C44-int 2, yellow oil, 1.8 g, 97.2%). MS (ESI) + m / z = 373.2[M+H] + .

[0428] Step 2: Under nitrogen protection, (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 2 N 4 Dimethylpyridine-2,3,4-triamine (1.6 g, 4.3 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of 1-chloro-2-methyl-1-oxopropyl-2-ylacetate (0.78 g, 4.7 mmol) and triethylamine (0.87 g, 8.6 mmol). The mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (500 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined and extracted with saturated brine (20 mL). L) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain (S)-1-((2-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)amino)-2-methyl-1-oxopropyl-2-yl acetate (yellow oil, 2.0 g, 93.0%). MS (ESI) + m / z = 501.3[M+H] + .

[0429] Step 3: Under nitrogen protection, (S)-1-((2-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)amino)-2-methyl-1-oxopropyl-2-yl acetate (2.0 g, 4.0 mmol) was dissolved in methanol (20 mL), potassium carbonate (0.55 g, 4.0 mmol) was added, and the mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain (S)-N-(2-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (yellow oil, 1.8 g, 97.2%). MS (ESI) + m / z = 495.3 [M+H]+ .

[0430] Step 4: Under nitrogen protection, (S)-N-(2-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (1.6 g, 3.5 mmol) was dissolved in a mixed solution of acetic acid and 1,4-dioxane (v / v = 1 / 5, 20 mL), and the solution was heated to 80 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was adjusted to pH 8-9 with sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was 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 petroleum ether / ethyl acetate (20 / 1-2 / 1) to obtain (S)-2-(4-((4-tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)prop-2-ol (yellow oil, 1.0 g, 64.8%). MS (ESI) + m / z = 441.3[M+H] + .

[0431] Intermediate C45.N 2 -((1r,3r)-3-((tert-butyldimethylsiloxy)methyl)cyclobutyl)-6-chloro-N 2 N 4 Preparation of 2,4-dimethyl-3-nitropyridine-2,4-diamine

[0432] Using intermediate C8 as a raw material, N was prepared according to the first step of the synthesis of intermediate B1. 2 -((1r,3r)-3-((tert-butyldimethylsiloxy)methyl)cyclobutyl)-6-chloro-N 2 N 4 2,4-Dimethyl-3-nitropyridine-2,4-diamine (yellow oil, 3 g, 94.6%). MS (ESI) + m / z = 415.2[M+H] + .

[0433] Intermediate C46.(S)-5-bromo-N 1 -(5-(tert-butyldimethylsiloxy)pent-2-yl)-N 1 N 3 Preparation of 1,3-dimethyl-2-nitrobenzene-1,3-diamine

[0434] Step 1: 5-Bromo-1,3-difluoro-2-nitrobenzene (5 g, 21.0 mmol) was dissolved in tetrahydrofuran (50 mL), and cesium carbonate (20.53 g, 63.0 mmol) and methylamine hydrochloride (1.42 g, 21.0 mmol) were added. The mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (50 / 1-10 / 1) to obtain 5-bromo-3-fluoro-N-methyl-2-nitrobenzene (yellow solid, 2 g, 38.2%). MS (ESI) + m / z = 249.1 [M+H] + .

[0435] Step 2: Under nitrogen protection, 5-bromo-3-fluoro-N-methyl-2-nitroaniline (2 g, 8.03 mmol) was dissolved in 1,4-dioxane (20 mL), and intermediate B5 (2.78 g, 12.0 mmol) and N,N-diisopropylethylamine (3.10 g, 24.1 mmol) were added. The mixture was microwaved to 120 °C and stirred for 2 h. After the reaction was complete, it was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (50 / 1-2 / 1) to obtain (S)-5-bromo-N 1 -(5-(tert-butyldimethylsiloxy)pent-2-yl)-N 1 N 3 1,3-Dimethyl-2-nitrobenzene-1,3-diamine (brown solid, 1.5 g, 40.5%). MS (ESI) + m / z = 460.2[M+H] + .

[0436] Preparation of intermediate C47.(S)-1-(4-(((S)-4-(benzyloxy)but-2-yl)(methyl)amino)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)ethyl acetate

[0437] Step 1: Using (S)-3-((3-amino-6-chloro-4-(methylamino)pyridin-2-yl)(methyl)amino)but-1-ol (C43-int 2) as the starting material, prepare (S)-N... 2-(4-(benzyloxy)but-2-yl)-6-chloro-N 2 N 4 -Dimethylpyridine-2,3,4-triamine (1.5 g). MS (ESI) + m / z = 449.2[M+H] + .

[0438] Step 2: (S)-N 2 -(4-(benzyloxy)but-2-yl)-6-chloro-N 2 N 4 Dimethylpyridine-2,3,4-triamine (1.5 g, 4.30 mmol) was dissolved in THF (15 mL), and TEA (1.3 g, 12.90 mmol) was added. The mixture was cooled to 0 °C, and intermediate H6 (0.64 g, 1.0 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 1 h. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-1-((2-(((S)-4-(benzyloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)amino)-1-oxopropyl-2-yl acetate (brown oil, 2.2 g, crude product). MS (ESI) + m / z = 463.2[M+H] + .

[0439] Step 3: Using (S)-1-((2-(((S)-4-(benzyloxy)but-2-yl)(methyl)amino)-6-chloro-4-(methylamino)pyridin-3-yl)amino)-1-oxopropyl-2-yl acetate as the starting material, ethyl acetate (yellow oil, 1.1 g, two-step yield: 57.5%) was prepared according to the method in Step 4 of the synthesis of intermediate C44. MS(ESI) + m / z = 445.0 [M+H] + .

[0440] Preparation of intermediate C48.(R)-1-(4-(((S)-3-(benzyloxy)-2-methylpropyl)(methyl)amino)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)ethyl acetate

[0441] Step 1: Intermediate C6 (1.9 g, 5.01 mmol) was dissolved in methanol (10 mL), and ammonium formate (1.58 g, 25.07 mmol) and zinc powder (1.63 g, 25.07 mmol) were added. The mixture was heated to 65 °C and stirred for 1 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL), and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 1) as eluent to obtain (S)-N 2 -(3-(benzyloxy)-2-methylpropyl)-6-chloro-N 2 N 4 2,3,4-Dimethylpyridine-2,3,4-triamine (yellow oil, 1.7 g, 97.2%). MS (ESI) + m / z = 349.2[M+H] + .

[0442] Steps 2 and 3: Using (S)-N 2 -(3-(benzyloxy)-2-methylpropyl)-6-chloro-N 2 N 4 Using dimethylpyridine-2,3,4-triamine and intermediate H7 as starting materials, ethyl acetate (R)-1-(4-(((S)-3-(benzyloxy)-2-methylpropyl)(methyl)amino)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl) was prepared according to the second and third steps of the synthesis of intermediate C47 (yellow oil, 1.6 g, two-step yield: 73.8%). MS (ESI) + m / z = 445.0 [M+H] + .

[0443] Intermediate C49.N 4 -((S)-4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 4 ,1-Dimethyl-N 2 Preparation of -(tetrahydrofuran-3-yl)-1H-imidazo[4,5-c]pyridine-2,4-diamine

[0444] With (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 2 N 4 Using dimethylpyridine-2,3,4-triamine (C44-int 2) and intermediate G2 as starting materials, N was prepared according to the method for synthesizing final product 33. 4-((S)-4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 4 ,1-Dimethyl-N 2 -(tetrahydrofuran-3-yl)-1H-imidazo[4,5-c]pyridine-2,4-diamine (yellow solid, 550 mg, 27.2%). MS (ESI) + m / z = 468.2[M+H] + .

[0445] Intermediate C50.N 4 -(4-(tert-butyldimethylsiloxy)butyl)-6-chloro-N 2 N 4 Preparation of 1-trimethyl-1H-imidazo[4,5-c]pyridine-2,4-diamine

[0446] Step 1: Using intermediate C7 as the starting material, 4-((3-amino-6-chloro-4-(methylamino)pyridin-2-yl)(methyl)amino)but-1-ol (yellow solid, 1.5 g, 83.8%) was prepared following the method used in Step 1 for the synthesis of intermediate C48. MS (ESI) + m / z = 259.2[M+H] + .

[0447] Steps 2 and 3: Using 4-((3-amino-6-chloro-4-(methylamino)pyridin-2-yl)(methyl)amino)but-1-ol and methyl isothiocyanate as raw materials, 4-((6-chloro-1-methyl-2-(methylamino)-1H-imidazo[4,5-c]pyridin-4-yl)(methyl)amino)but-1-ol (brown oil, 1 g, 50.7%) was prepared according to the method for synthesizing intermediate C49. MS (ESI) + m / z = 298.0 [M+H] + .

[0448] Step 4: Using 4-((6-chloro-1-methyl-2-(methylamino)-1H-imidazo[4,5-c]pyridin-4-yl)(methyl)amino)but-1-ol as the starting material, prepare N according to the method in step 1 of the synthesis of intermediate B1. 4 -(4-(tert-butyldimethylsiloxy)butyl)-6-chloro-N 2 N 4 1-Trimethyl-1H-imidazo[4,5-c]pyridine-2,4-diamine (yellow solid, 400 mg, 64.2%). MS (ESI) + m / z = 412[M+H] + .

[0449] Preparation of intermediate C51.(S)-1-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-3-chloro-6,7-dihydropyridine[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid benzyl ester

[0450] Using intermediates A15 and B1 as raw materials, (S)-1-((4-(tert-butyldimethylsiloxy)but-2-yl)(methyl)amino)-3-chloro-6,7-dihydropyridine[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-formate benzyl ester (yellow solid, 150 mg, 33.8%) was prepared by following the method for synthesizing intermediate C40. MS(ESI) + m / z = 558.3 ​​[M+H] + .

[0451] Preparation of intermediate C52.(S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N,1-dimethyl-2-((methylthio)methyl)-1H-imidazo[4,5-c]pyridine-4-amine

[0452] Step 1, Step 2: Using (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N 2 N 4 Using dimethylpyridine-2,3,4-triamine (C44-int 2) and 2-chloroacetic anhydride as starting materials, (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-2-(chloromethyl)-N,1-dimethyl-1H-imidazo[4,5-c]pyridine-4-amine (yellow oil, 1.4 g, crude product) was prepared according to the second and third steps of the synthesis of intermediate C47. MS(ESI) + m / z = 431.1[M+H] + .

[0453] Step 3: Dissolve (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-2-(chloromethyl)-N,1-dimethyl-1H-imidazo[4,5-c]pyridine-4-amine (1.40 g, 3.24 mmol) in DMF (40 mL), add sodium methanethiol (286 mg, 4.08 mmol), and stir at room temperature for 1 h. After the reaction was complete, water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1) as eluent to obtain (S)-N-(4-(tert-butyldimethylsiloxy)but-2-yl)-6-chloro-N,1-dimethyl-2-((methylthio)methyl)-1H-imidazo[4,5-c]pyridine-4-amine (brown solid, 560 mg, three-step yield: 31.4%). MS (ESI) + m / z = 443.2[M+H] + .

[0454] Preparation of intermediate C54. 4-(1-(6-chloro-4-(methylamino)-3-nitropyridin-2-yl)pyrrolidine-2-yl)but-2-ol

[0455] Step 1: Under nitrogen protection, (tert-butyloxycarbonyl)proline (5g, 116.28mmol) was dissolved in dichloromethane (350mL), and then iodotrimethylbenzene (12.8g, 58.14mmol), Ni(acac)2 (299mg, 1.16mmol), potassium tri(pyrazolyl)borate (391mg, 1.16mmol), thioxanone (493mg, 2.33mmol), and 4-oxovalerate (13.5g, 23.26mmol) were added sequentially. The mixture was stirred at room temperature under blue light for three days. After the reaction was complete, water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined and washed with saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-(3-oxobutyl)pyrrolidine-1-carboxylate (2.06 g, crude product). MS (ESI) + m / z = 242.1[M+H] + .

[0456] Step 2: Dissolve 2-(3-oxobutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.01 g, 8.34 mmol) in tetrahydrofuran (20 mL), cool to 0 °C, add sodium borohydride (950 mg, 25.02 mmol), and heat to 25 °C with stirring for 1 h. After the reaction is complete, add sodium hydroxide aqueous solution (1 M, 25 mL) to the reaction solution. Extract the mixture with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-3 / 1) to obtain 2-(3-hydroxybutyl)pyrrolidine-1-carboxylic acid tert-butyl ester (colorless oil, 1.43 g). + m / z = 244.1[M+H] + .

[0457] Step 3: Dissolve 1.4 g (5.76 mmol) of tert-butyl 2-(3-hydroxybutyl)pyrrolidine-1-carboxylate in 12 mL of dichloromethane, cool to 0 °C, add 4 mL of trifluoroacetic acid, and heat to room temperature with stirring for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain 1.6 g of 4-(pyrrolidine-2-yl)but-2-ol, which is used directly in the next step without purification. MS (ESI) + m / z = 143.1 [M+H] + .

[0458] Step 4: Using intermediate A11, 2,6-dichloro-N-methyl-3-nitropyridin-4-amine, and 4-(pyrrolidone-2-yl)but-2-ol as starting materials, 4-(1-(6-chloro-4-(methylamino)-3-nitropyridin-2-yl)pyrrolidone-2-yl)but-2-ol (yellow solid, 220 mg, 24%) was prepared following the method used in Step 1 for the synthesis of intermediate A15. MS (ESI) + m / z = 329.0 [M+H] + .

[0459] Preparation of intermediates D1-D25 in the fourth preparation example

[0460] Preparation of intermediate D1. 6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine

[0461] Step 1: Under nitrogen protection, ethyl 4,6-dichloro-2-methylnicotinate (25.0 g, 0.11 mol) was dissolved in tetrahydrofuran (500 mL), cooled to 0 °C, and DIBAL-H (235 mL, 0.23 mol) was added. The mixture was then heated to 25 °C and stirred for 4 h. After the reaction was complete, ammonium chloride solution (750 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with petroleum ether / ethyl acetate (30 / 1), filtered, and the residue was dried to obtain (4,6-dichloro-2-methylpyridin-3-yl)methanol (white solid, 17 g, 82.9%). MS (ESI) + m / z = 192.0 [M+H] + .

[0462] Step 2: Dissolve (17.0 g, 0.088 mol) of (4,6-dichloro-2-methylpyridin-3-yl)methanol in dichloromethane (170 mL), add Dysmartin oxidant (41.3 g, 0.097 mmol), and stir at room temperature for 3 h. After the reaction is complete, add sodium bicarbonate solution (300 mL) to the reaction solution, extract the mixture with dichloromethane (200 mL × 3), combine the organic phases and wash with saturated brine (200 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using a gradient elution of ethyl acetate / petroleum ether (1 / 100-1 / 20) to obtain 4,6-dichloro-2-methylnicotinaldehyde (white solid, 12 g, 71.4%). MS (ESI) + m / z = 190.1[M+H] + .

[0463] Step 3: Dissolve 4,6-dichloro-2-methylnicotinaldehyde (24.0 g, 0.13 mol) in DMA (240 mL), cool to 0 °C, add 85% hydrazine hydrate (37.2 g, 0.63 mol), heat to 80 °C and stir for 3 h. After the reaction is complete, cool to room temperature, add water (300 mL) to the reaction solution, extract the mixture with ethyl acetate (300 mL × 3), combine the organic phases and wash with saturated brine (300 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-10 / 1) to obtain 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 18 g, 85.0%). MS (ESI) + m / z = 168.1 [M+H] + .

[0464] Step 4: Under nitrogen protection, 18.0 g (0.11 mol) of 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridine was dissolved in 180 mL of DMF. The solution was cooled to 0 °C, and 5.7 g (0.14 mol) of 60% NaH was added. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of p-toluenesulfonyl chloride (26.6 g, 0.14 mol). The mixture was then heated to room temperature and stirred for 3 h. After the reaction was complete, 300 mL of saturated sodium chloride solution was added to the reaction solution. The mixture was filtered, and the residue was slurried with petroleum ether / ethyl acetate (5 / 1), filtered, and dried to obtain 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 25 g, 72.3%). MS (ESI) + m / z = 322.0 [M+H] + .

[0465] Step 5: Under nitrogen protection, 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (10.0 g, 31.08 mmol) was dissolved in a mixture of 1,4-dioxane (100 mL) and water (100 mL). 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-pyridine (8.8 g, 37.29 mmol), Pd(dppf)Cl2 (2.3 g, 3.11 mmol), and cesium carbonate (25.3 g, 77.69 mmol) were added, and the mixture was heated to 100 °C and stirred for 8 h. After the reaction was complete and cooled to room temperature, water (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether, filtered, and the residue was dried to give 6-(4-methoxypyridin-3-yl)-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (brown solid, 9 g, 71.8%). MS (ESI) + m / z = 395.2[M+H] + .

[0466] Step 6: Dissolve 24.0 g (0.061 mol) of 6-(4-methoxypyridin-3-yl)-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine in a mixture of 110 mL THF and 110 mL water. Cool to 0 °C, add 21.9 g (0.55 mol) of sodium hydroxide, and heat to 30 °C with stirring for 6 h. After the reaction is complete, concentrate the reaction solution under reduced pressure. Adjust the pH of the residue to 8-9 with 6 M hydrochloric acid, filter, and dry the filter residue to obtain 6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 12 g, 82.3%). MS (ESI) + m / z = 241.1[M+H] + .

[0467] Preparation of intermediate D2. 6-(2-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine

[0468] 6-(2-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 300 mg, 82.4%) was prepared from 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine and (2-methoxyphenyl)boronic acid according to steps five and six of the synthetic intermediate D1. MS (ESI) + m / z = 240.7[M+H] + .

[0469] Preparation of intermediates D3-D8

[0470] Intermediates D3-D4 and D7-D8 were prepared using 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine and commercially available boric acid or boron ester compounds as starting materials, following the method used to synthesize intermediate D2. The reaction conditions for the first step were: Pd(OAc)2, CataXCium A, B2pin2, Cs2CO3, 1,4-dioxane, 100℃. The solvent for the second step of deprotection was DMSO.

[0471] Intermediates D5-D6 were prepared using ethyl 2,3-dichloro-5-nicotinic acid as the starting material and commercially available boric acid or boron ester compounds as raw materials, following the method used to synthesize intermediate D1. The reaction conditions for step five were: Pd(OAc)2, CataXCium A, B2pin2, Cs2CO3, 1,4-dioxane, 100℃. The deprotection solvent for step six was DMSO. See Table 3 for details.

[0472] Table 3. Structural and characterization data of intermediates D3-D8

[0473] Preparation of intermediate D9. 6-(4-methoxy-2-methylpyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine

[0474] Step 1: Using 4-hydroxy-2-methylpyridine and NBS as starting materials, 3-bromo-2-methylpyridine-4-ol (white solid, 11 g, 25.6%) was prepared according to the method described in Step 2 of the synthesis of intermediate D24. MS (ESI) + m / z = 187.9 [M+H] + .

[0475] Step 2: Under nitrogen protection, 3-bromo-2-methylpyridin-4-ol (11 g, 58.5 mmol) was dissolved in 1,4-dioxane (100 mL), and phosphorus oxychloride (20 mL, 268.8 mmol) was added dropwise. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was adjusted to pH 7-8 with saturated sodium carbonate aqueous solution (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (200 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 petroleum ether / ethyl acetate (10 / 1-5 / 1) to obtain 3-bromo-4-chloro-2-methylpyridine (yellow solid, 9 g, 74.5%). + m / z = 205.9[M+H] + .

[0476] Step 3: Under nitrogen protection, 3-bromo-4-chloro-2-methylpyridine (9 g, 43.9 mmol) was dissolved in methanol (100 mL), and sodium methoxide (23.6 g, 437 mmol) was added. The mixture was heated to 70 °C and stirred for 16 h. After the reaction was complete, ice water (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (300 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (10 / 1-5 / 1) to obtain 3-bromo-4-methoxy-2-methylpyridine (yellow solid, 6 g, 68.1%). MS (ESI) + m / z = 202.0[M+H] + .

[0477] Step 4: Under nitrogen protection, 3-bromo-4-methoxy-2-methylpyridine (6.5 g, 32.3 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (v / v = 10 / 1, 120 mL), and 6-chloro-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (10.4 g, 32.3 mmol), pinacol diborate (16.4 g, 64.6 mmol), palladium acetate (0.72 g, 3.18 mmol), n-butyldi(1-adamantyl)phosphine (2.3 g, 6.42 mmol), and cesium carbonate (31.5 g, 96.6 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 8 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and water (200 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-30 / 1) to obtain 6-(4-methoxy-2-methylpyridin-3-yl)-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 5 g, 37.9%). MS (ESI) + m / z = 409.9 [M+H] + .

[0478] Step 5: Using 6-(4-methoxy-2-methylpyridin-3-yl)-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine as the starting material, 6-(4-methoxy-2-methylpyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 4.2 g, crude product) was prepared according to the method in Step 6 of the synthesis intermediate D1. MS (ESI) + m / z = 255.1 [M+H] + .

[0479] Preparation of intermediate D10. 6-(4-methoxy-6-methylpyridin-3-yl)-4-methyl-1H-pyrazole[4,3-c]pyridine

[0480] Step 1: Under nitrogen protection, 5-bromo-4-methoxy-2-methylpyridine (9 g, 0.04 mol) was dissolved in 1,4-dioxane (90 mL), and bis(boron)pinacol ester (22.6 g, 0.09 mol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (3.26 g, 0.004 mol), and potassium acetate (8.73 g, 0.09 mol) were added. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 4-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (brown solid, 30 g, crude product). MS (ESI) + m / z = 250.1[M+H] + .

[0481] Steps 2 and 3: Using 4-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine and 6-chloro-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine as starting materials, 6-(4-methoxy-6-methylpyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (brown solid, 4.6 g, crude product) was prepared according to steps 5 and 6 of the synthesis intermediate D1. MS(ESI) + m / z = 253.2[M+H] + .

[0482] Preparation of intermediate D11. 2-methyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0483] Step 1: 2-Methyl-1,2-dihydro-3H-pyrazol-3-one (20.0 g, 0.20 mol) was dissolved in tetrahydrofuran (300 mL), and potassium carbonate (112.7 g, 0.82 mol) and SEMCl (51.0 g, 0.31 mol) were added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 37 g, 79.1%). MS (ESI) + m / z = 229.2[M+H]+ .

[0484] Step 2: Dissolve 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (20.0 g, 0.088 mol) in acetonitrile (300 mL), cool to 0 °C, add NBS (20.3 g, 0.11 mol) in portions, and stir at room temperature for 2 h. After the reaction was complete, saturated sodium thiosulfate solution (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (150 / 1-50 / 1) to obtain 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (intermediate A18, yellow solid, 7.5 g, 27.9%). MS (ESI) + m / z = 306.9 [M+H] + .

[0485] Step 3: Under nitrogen protection, 6-chloro-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (5.0 g, 15.54 mmol) was dissolved in a mixture of 1,4-dioxane (100 mL) and water (10 mL). Then, 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (7.2 g, 23.31 mmol), palladium acetate (704.0 mg, 3.11 mmol), n-butyldi(1-adamantyl)phosphine (557.1 mg, 1.55 mmol), pinacol diboronate (7.9 g, 31.08 mmol), and cesium carbonate (25.3 g, 77.69 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 2 h. After the reaction was complete and cooled to room temperature, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 2-methyl-4-(4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 2.5 g, 31.3%). MS (ESI) + m / z = 514.2[M+H] + .

[0486] Step 4: Using 2-methyl-4-(4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (1.0 g, 1.95 mmol) as the starting material, 2-methyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 0.5 g, 74.3%) was prepared according to the method in Step 6 of Intermediate D1. MS (ESI) + m / z = 360.2[M+H] + .

[0487] Preparation of intermediate D12. 2,5-dimethyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0488] Using 2,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (30.0 g, 0.27 mol) and SEMCl (66.9 g, 0.40 mol) as starting materials, 2,5-dimethyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (white solid, 3.2 g, 75.2%) was prepared according to the method for synthesizing intermediate D11. MS (ESI) + m / z = 374.3 [M+H] + .

[0489] Preparation of intermediate D13. 2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0490] Step 1: Using 6-chloro-1H-pyrazolo[4,3-c]pyridine (22.0 g, 0.14 mmol) (the product obtained in step 3 of the preparation of intermediate D5) as the starting material, 6-chloro-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 20 g, 45.2%) was prepared according to the method in step 4 of the synthesis of intermediate D1. MS (ESI) + m / z = 308.0 [M+H] + .

[0491] Steps 2 and 3: Using 6-chloro-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine and 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as starting materials, 2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 950 mg, 54.9%) was prepared according to the methods of steps 3 and 4 of the synthesis of intermediate D11. MS(ESI) + m / z = 346.2[M+H] + .

[0492] Preparation of intermediate D14. 2,5-dimethyl-4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0493] Using 4-bromo-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (the product obtained in the second step of the preparation of intermediate D12) and 6-chloro-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine as starting materials, 2,5-dimethyl-4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (white solid, 1.7 g, 17.9%) was prepared by following the methods in the third and fourth steps of the synthesis of intermediate D11. MS (ESI) + m / z = 360.3[M+H] + .

[0494] Preparation of intermediate D15. 2-Cyclopropyl-4-(4-methyl-1H-pyrazol[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0495] Step 1: Dissolve cyclopropanehydrazine hydrochloride (60 g, 0.55 mol) in methanol (600 mL), add methyl 3-methoxyacrylate (64.2 g, 0.55 mol), and heat to 60 °C with stirring for 6 h. After the reaction is complete, cool to room temperature, concentrate the reaction solution under reduced pressure, and slurry the resulting residue with tetrahydrofuran (200 mL), filter, collect the filter residue to obtain the crude product, and then purify the crude product by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 2-cyclopropyl-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 29 g, 42.3%). MS (ESI) + m / z = 125.2[M+H] + .

[0496] Step 2: Dissolve 2-cyclopropyl-1,2-dihydro-3H-pyrazol-3-one (28g, 0.23mol) in acetonitrile (300mL), add potassium carbonate (125g, 0.9mol) and SEMCl (56.4g, 0.34mol), and stir at 25℃ for 16h. After the reaction was complete, water (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed successively with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (yellow solid, 10 g, 20.2%). MS (ESI) + m / z = 256.2[M+H] + .

[0497] Step 3: Using 2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one as the starting material, 4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (yellow solid, 6 g, 45.9%) was prepared according to the method in Step 2 of the synthesis of intermediate D11. MS (ESI) + m / z = 333.1[M+H] + .

[0498] Step 4: Using 4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one and 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine as starting materials, 2-cyclopropyl-4-(4-methyl-1-toluenesulfonyl-1H-pyrazol[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 1.4 g, 45.1%) was prepared according to the method in Step 3 of the synthesis of intermediate D11. MS (ESI) + m / z = 450.3[M+H] + .

[0499] Step 5: Using 2-cyclopropyl-4-(4-methyl-1-toluenesulfonyl-1H-pyrazole[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one as the starting material, 2-cyclopropyl-4-(4-methyl-1H-pyrazole[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazole-3-one (yellow solid, 0.4 g, 58.5%) was prepared according to the method in Step 6 of the synthesis of intermediate D1. MS (ESI) + m / z = 386.3 [M+H] + .

[0500] Preparation of intermediate D16. 4-ethyl-6-(4-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine

[0501] Step 1: Dissolve ethyl propionyl acetate (15 g, 0.10 mol) in methanol (200 mL), add ammonium acetate (40 g, 0.52 mol), and stir at 25 °C for 24 h. After the reaction is complete, concentrate the reaction solution under reduced pressure, dilute the residue with water (600 mL), extract the mixture with dichloromethane (200 mL × 3), combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain ethyl 3-aminopentane-2-enoate (yellow oil, 14 g, 94%).

[0502] Step 2: Under nitrogen protection, ethyl 3-aminopent-2-enoate (5.5 g, 8.4 mmol) was dissolved in bromobenzene (50 mL), and bis(2,4,6-trichlorophenyl)malonic acid (17.8 g, 38.4 mmol) was added. The mixture was heated to 155 °C and stirred for 1 h. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (50 / 1-20 / 1) to obtain ethyl 2-ethyl-4,6-dihydroxynicotinic acid (yellow solid, 3.8 g, 46.9%). MS (ESI) + m / z = 212.3[M+H] + .

[0503] Step 3: Under nitrogen protection, ethyl 2-ethyl-4,6-dihydroxynicotinic acid (3.8 g, 18.0 mmol) was dissolved in phosphorus oxychloride (30 mL), and the mixture was heated to 120 °C and stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with dichloromethane (100 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-10 / 1) to obtain ethyl 4,6-dichloro-2-ethylnicotinic acid (yellow oil, 2.4 g, 53.8%). MS (ESI) + m / z = 247.9 [M+H] + .

[0504] Steps 4 through 9: Using ethyl 4,6-dichloro-2-ethylnicotinate as a starting material, 4-ethyl-6-(4-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (yellow solid, 0.6 g, 87.6%) was prepared according to the method for synthesizing intermediate D1. MS (ESI) + m / z = 255.1 [M+H] + .

[0505] Preparation of intermediate D17. 4-Cyclopropyl-6-(4-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine

[0506] Step 1: Under nitrogen protection, 4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (5 g, 16.2 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (v / v = 10 / 1, 50 mL), and cyclopropylboronic acid (4.17 g, 48.67 mmol), Pd(PPh3)4 (1.87 g, 1.62 mmol), and sodium carbonate (4.29 g, 40.5 mmol) were added. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (50 mL) was added to the reaction solution, and the mixture was filtered. The filtrate was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (white solid, 2.5 g, 49.4%). MS (ESI) + m / z = 314.0 [M+H] + .

[0507] Step 2: Using 6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine and 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine as starting materials, 4-cyclopropyl-1-(4-methoxybenzyl)-6-(4-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (yellow solid, 1.6 g, 86.6%) was prepared according to the method in step 5 of the synthesis of intermediate D1. MS(ESI) + m / z = 387.1 [M+H] + .

[0508] Step 3: 4-Cyclopropyl-1-(4-methoxybenzyl)-6-(4-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (1.6 g, 4.14 mmol) was dissolved in TFA (10 mL), and the mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was adjusted to pH 10 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-cyclopropyl-6-(4-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (brown solid, 1.2 g, crude product). MS (ESI) + m / z = 267.1 [M+H] + .

[0509] Preparation of intermediate D18. 4-(4-ethyl-1H-pyrazol[4,3-c]pyridin-6-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0510] Using 6-chloro-4-ethyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine and 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as starting materials, 4-(4-ethyl-1H-pyrazol[4,3-c]pyridin-6-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 0.8 g, 75.5%) was prepared according to the third and fourth steps of the synthesis of intermediate D11. MS (ESI) + m / z = 374.3 [M+H] + .

[0511] Preparation of intermediate D19. 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0512] Step 1 and Step 2: Dissolve 2,2,2-trifluoroacetamide (100.63 g, 890.2 mmol) in pyridine (700 mL), and add dropwise a pyridine (300 mL) solution containing trifluoroacetic anhydride (186.96 g, 890.2 mmol) to generate trifluoroacetonitrile gas. Pass the generated gas into a mixture of diethyl 1,3-propanone dicarboxylate (90 g, 445.1 mmol) and potassium tert-butoxide (52.44 g, 467.3 mmol) in tetrahydrofuran (900 mL), and stir at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The resulting residue was adjusted to pH 3 with 4M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was slurried with dichloromethane (100 mL), filtered, and the residue was dried to obtain ethyl 4,6-dihydroxy-2-(trifluoromethyl)nicotinic acid (white solid, 65 g, 58.2%). MS (ESI) + m / z = 252.0 [M+H] + .

[0513] Steps 3 to 6: Using ethyl 4,6-dichloro-2-(trifluoromethyl)nicotinate as a starting material, 6-chloro-4-trifluoromethyl-1H-pyrazolo[4,3-c]pyridine (yellow solid, 12 g, 88.2%) was prepared according to the method described in steps 3 to 6 of the synthesis of intermediate D16. MS (ESI) + m / z = 222.0[M+H] + .

[0514] Steps 7 to 9: Using 6-chloro-4-trifluoromethyl-1H-pyrazolo[4,3-c]pyridine as a starting material, 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 0.43 g, 39.4%) was prepared by following the method for synthesizing intermediate D13. MS (ESI) + m / z = 414.2[M+H] + The reaction conditions for step eight are: Pd(OAc)2, CataXCium A, B2pin2, K2CO3, 1,4-dioxane, 100℃.

[0515] Preparation of intermediate D20. 4-(4-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0516] Step 1: Using 6-chloro-4-cyclopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine as the starting material, 6-chloro-4-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (brown solid, 8 g, crude product) was prepared according to the method in step 3 of the synthesis of intermediate D17. MS (ESI+) m / z = 194.0 [M+H] + .

[0517] Steps 2 to 4: Using 6-chloro-4-cyclopropyl-1H-pyrazolo[4,3-c]pyridine as a starting material, 4-(4-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 1 g, crude product) was prepared according to the method for synthesizing intermediate D13. MS (ESI+) m / z = 386.1 [M+H] + .

[0518] Preparation of intermediate D21. 2-methyl-4-(1H-pyrazol[3,4-d]pyrimidin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0519] 2-Methyl-4-(1H-pyrazolo[3,4-D]pyrimidine)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 600 mg, 34.6%) was prepared from 6-chloro-1H-pyrazolo[3,4-d]pyrimidine using the method for synthesizing intermediate D13. MS (ESI) + m / z = 347.0 [M+H] + .

[0520] Preparation of intermediate D22. 2-methyl-4-(1H-pyrazolo[4,3-c]pyridazin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0521] Step 1: Methyl 4,6-dichloropyridazine-3-carboxylate (45.0 g, 0.22 mol) was dissolved in ethanol (500 mL), cooled to 0 °C, and 80% hydrazine hydrate (13.6 g, 0.22 mol) was added dropwise. The mixture was stirred at 0 °C for 2 h. After the reaction was complete, the mixture was allowed to return to room temperature. The reaction solution was concentrated under reduced pressure. The resulting residue was slurried with methyl tert-butyl ether (500 mL), filtered, and the filter residue was dried to obtain methyl 6-chloro-4-hydrazidopyridazine-3-carboxylate (yellow solid, 24.0 g, 54.5%). MS (ESI+) m / z = 203.0 [M+H] + .

[0522] Step 2: Under nitrogen protection, methyl 6-chloro-4-hydrazinopyridazine-3-carboxylate (23.0 g, 0.11 mol) was dissolved in dichloromethane (500 mL), cooled to -78 °C, and diisobutylaluminum hydride (1 M, 227 mL, 0.23 mol) was added dropwise. The mixture was then slowly heated to 25 °C and stirred for 4 h. After the reaction was complete, ammonium chloride solution (200 mL) was added to the reaction solution, filtered, and the filtrate was extracted with dichloromethane (200 mL × 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6-chloro-1H-pyrazolo[4,3-c]pyridazine (yellow solid, 7.0 g, 39.9%). MS (ESI+) m / z = 154.9 [M+H] + .

[0523] Steps 3 to 5: Using 6-chloro-1H-pyrazolo[4,3-c]pyridazine as a starting material, 2-methyl-4-(1H-pyrazolo[4,3-c]pyridazine-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 0.56 g, 53.9%) was prepared according to the method for synthesizing intermediate D13. MS (ESI) + m / z = 347.1 [M+H] + .

[0524] Preparation of intermediate D23. 4-methyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrazol[4,3-c]pyridine

[0525] Step 1: Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole as the starting material, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (yellow oil, 4 g, 47.9%) was prepared according to the method for synthesizing intermediate A5. MS (ESI) + m / z = 325.2[M+H] + .

[0526] Step 2: Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.90 g, 15.1 mmol) was dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). 6-chloro-4-methyl-1-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine (4.85 g, 15.1 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (0.5 g, 0.76 mmol), and sodium carbonate (4.8 g, 45.3 mmol) were added, and the mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-5 / 1) to obtain 4-methyl-1-toluenesulfonyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrrole[4,3-c]pyridine (yellow solid, 3.5 g, 47.9%). MS (ESI) + m / z = 484.2[M+H]+ .

[0527] Step 3: Using 4-methyl-1-toluenesulfonyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-1H-pyrrolo[4,3-c]pyridine as the starting material, 4-methyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-1H-pyrazole[4,3-c]pyridine (yellow solid, 1.8 g, 75.5%) was prepared according to the method in step 6 of the synthesis intermediate D1. MS(ESI) + m / z = 325.2[M+H] + .

[0528] Preparation of intermediate D24. 4-methoxy-N,N-dimethyl-5-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyridine-2-amine

[0529] Step 1: Using 2-amino-4-methoxypyridine and an aqueous formaldehyde solution as raw materials, 4-methoxy-N,N-dimethylpyridine-2-amine (yellow oil, 17 g, 69.3%) was prepared according to the method in step 3 of the synthesis of intermediate A6. MS (ESI) + m / z = 153.1 [M+H] + .

[0530] Step 2: Under nitrogen protection, 4-methoxy-N,N-dimethylpyridine-2-amine (35 g, 0.23 mol) was dissolved in DMF (350 mL), cooled to 0 °C in an ice bath, and NBS (61.4 g, 0.35 mol) was added in batches. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, saturated sodium thiosulfate solution (500 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane / methanol (50 / 1-20 / 1) as the eluent to obtain 5-bromo-4-methoxy-N,N-dimethylpyridine-2-amine (yellow solid, 32 g, 60.4%). MS (ESI) + m / z = 233.0 [M+H] + .

[0531] Steps 3 and 4: Using 5-bromo-4-methoxy-N,N-dimethylpyridin-2-amine and 6-chloro-4-methyl-1-p-toluenesulfonyl-1H-pyrazolo[4,3-c]pyridine as starting materials, 4-methoxy-N,N-dimethyl-5-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyridin-2-amine (yellow solid, 2.2 g, 68.1%) was prepared according to the methods described in steps 3 and 4 of the synthesis of intermediate D11. MS (ESI) + m / z = 284.1 [M+H] + .

[0532] Preparation of intermediate D25. 4-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0533] Step 1: Using 5-chloro-1H-pyrazolo[3,4-c]pyridine as a starting material, 5-chloro-1H-pyrazolo[3,4-c]pyridine (yellow solid, 22 g, 55%) was prepared according to the method in step 4 of the synthesis intermediate D1. MS (ESI) + m / z = 309.9 [M+H] + .

[0534] Step 2: Using intermediate A18 and 5-chloro-1-toluenesulfonyl-1H-pyrazolo[3,4-c]pyridine as raw materials, 2-methyl-4-(1-toluenesulfonyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 5.5 g, 22.6%) was prepared according to the method in Step 3 of the synthesis of intermediate D11. MS(ESI) + m / z = 500.3[M+H] + .

[0535] Step 3: Using 2-methyl-4-(1-toluenesulfonyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one as the starting material, 2-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 6.5 g, 85.5%) was prepared according to the method in Step 6 of the synthesis of intermediate D1. MS(ESI) + m / z = 346.2[M+H] + .

[0536] Step 4: Dissolve 2-methyl-4-(1H-pyrazolo[3,4-c]pyridin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (6.5 g, 18.8 mmol) in DMF (65 mL), add potassium hydroxide (3.69 g, 65.85 mmol) and iodine (9.54 g, 37.6 mmol), and stir at 25 °C for 2 h. After the reaction is complete, add water (100 mL) to the reaction solution, and dilute the mixture with ethyl acetate (30 mL). Extracted by L×3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 4-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 6 g, 67.7%). MS (ESI) + m / z = 472.0 [M+H] + .

[0537] Step 5: Under nitrogen protection, 4-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (6 g, 12.7 mmol) was dissolved in dichloromethane (60 mL), methanesulfonic acid (1.22 g, 12.7 mmol) was added, the temperature was lowered to 0 °C, 3,4-dihydro-2H-pyran (2.14 g, 25.4 mmol) was added, and the temperature was raised to 25 °C and stirred for 16 h. After the reaction was complete, saturated sodium bicarbonate solution (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain 4-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 6 g, 85.7%). MS (ESI) + m / z = 555.6 [M+H] + .

[0538] Preparation of intermediates E1-E39 in the fifth preparation example.

[0539] Intermediate E1.(S)-N 1(4),2 4 7,8-Tetramethyl-2 1 H-4-oxa-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(6,2),3(3,4)-dipyridinecyclooctane-1 2 ,1 3 Preparation of -diamine

[0540] Step 1: Under nitrogen protection, intermediate C4 (5.0 g, 12.41 mmol) was dissolved in 1,4-dioxane (80 mL), followed by intermediate D1 (3.3 g, 13.65 mmol), Ephos Pd G4 (569.8 mg, 0.62 mmol), Ephos (663.5 mg, 1.24 mmol), and cesium carbonate (12.1 g, 37.22 mmol). The mixture was heated to 100 °C and stirred for 16 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 × 3), and the organic phases were combined and washed with saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-20 / 1) to obtain (S)-N. 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-(6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-N 2 N 4 2,4-Dimethyl-3-nitropyridine-2,4-diamine (yellow solid, 4 g, 56.4%). MS (ESI) + m / z = 607.3 [M+H] + .

[0541] Step 2: Under nitrogen protection, (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-(6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-N 2 N 4Dimethyl-3-nitropyridine-2,4-diamine (6.5 g, 10.71 mmol) was dissolved in tetrahydrofuran (65 mL), cooled to 0 °C, and 1 M TBAF solution in tetrahydrofuran (22 mL, 21.42 mmol) was added. The mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-3-((6-(6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(methylamino)-3-nitropyridin-2-yl)(methyl)amino)but-1-ol (yellow solid, 6 g, crude product). MS (ESI) + m / z = 493.2[M+H] + .

[0542] Step 3: Under nitrogen protection, (S)-3-((6-(6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(methylamino)-3-nitropyridin-2-yl)(methyl)amino)but-1-ol (11.0 g, 0.022 mol) was dissolved in tetrahydrofuran (150 mL), cooled to 0 °C, and boron tribromide (55.9 g, 0.22 mol) was slowly added dropwise. The mixture was then heated to 60 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, methanol (50 mL) was added to the reaction solution. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane / methanol (20 / 1) as eluent to obtain (S)-3-(1-(6-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyridin-4-ol (yellow solid, 7 g, 67.4%). MS (ESI) + m / z = 479.3 [M+H] + .

[0543] Step 4: Under nitrogen protection, (S)-3-(1-(6-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyridin-4-ol (5.2 g, 10.87 mmol) was dissolved in toluene (60 mL), and CMBP (13.1 g, 54.34 mmol) was added. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The resulting residue was slurried with methanol (50 mL), filtered, and the filter residue was dried to obtain (S)-N,2 4,7,8-Tetramethyl-1 3 -Nitro-2 1 H-4-oxa-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(6,2),3(3,4)-dipyridinecyclooctane-1 4 -Amine (yellow solid, 2g, 40.0%). MS (ESI) + m / z = 461.3[M+H] + .

[0544] Step 5: Under nitrogen protection, (S)-N,2 4 ,7,8-Tetramethyl-1 3 -Nitro-2 1 H-4-oxa-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(6,2),3(3,4)-dipyridinecyclooctane-1 4 (S)-N-amine (1.0 g, 2.17 mmol) was dissolved in dichloromethane (30 mL), and 10% Pd / C (577.8 mg, 0.55 mmol) was added to displace hydrogen gas. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-N-amine. 1(4) ,2 4 7,8-Tetramethyl-2 1 H-4-oxa-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(6,2),3(3,4)-dipyridinecyclooctane-1 2 ,1 3 2-Diamine (yellow solid, 700 mg, 74.9%). MS (ESI) + m / z = 431.3[M+H] + .

[0545] Preparation of intermediates E2-E15, E39

[0546] Using intermediates C4-C5, C9-C10, C12-C14, C16-C18 and D1, D5-D6, D8-D10, D16-D17 as raw materials, intermediates E2-E15 and E39 were prepared according to the method for synthesizing intermediate E1. The conditions for the third step were either: TsOH, LiCl, DMF, 120℃ or LiCl, p-toluenesulfonic acid, NMP, 80℃; the conditions for the fifth step reduction were either: B2(OH)4, 4,4'-bipyridine, DMF, room temperature. See Table 4 for details.

[0547] Table 4. Raw material, structure and characterization data of intermediates E2-E15 and E39

[0548] Intermediate E16.(S)-N 1(4) ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 ,1 5 Preparation of -diamine

[0549] Step 1: Under nitrogen protection, intermediate D12 (3.0 g, 8.03 mmol) was dissolved in 1,4-dioxane (40 mL), cooled to 0 °C, and intermediate C25 (4.0 g, 9.64 mmol), Ephos Pd G4 (0.74 g, 0.80 mmol), Ephos (0.86 g, 1.61 mmol) and cesium carbonate (7.9 g, 24.09 mmol) were added sequentially. The mixture was then heated to 100 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (1 / 100-1 / 20) to obtain (S)-4-(1-(6-((5-(tert-butyldimethylsiloxy)pentan-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyrazol-6-yl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (yellow solid, 4.8 g, 80.0%). MS (ESI) + m / z = 754.3 [M+H] + .

[0550] Step 2: Under nitrogen protection, (S)-4-(1-(6-((5-(tert-butyldimethylsiloxy)pentan-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyrazol-6-yl)-2,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (5.1 g, 6.76 mmol) was dissolved in THF (50 mL), and 1 M TBAF in tetrahydrofuran solution (34 mL, 33.82 mmol) was added. The mixture was heated to 70 °C and stirred for 4 h. After the reaction was complete and cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient elution of methanol / dichloromethane (1 / 100-1 / 20) to obtain (S)-4-(1-(6-((5-hydroxypentan-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyrazol-6-yl)-1,3-dimethyl-1H-pyrazol-5-ol (yellow solid, 3.1 g, 89.7%). MS (ESI) + m / z = 510.3[M+H] + .

[0551] Step 3: Under nitrogen protection, (S)-4-(1-(6-((5-hydroxypentan-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyrazol-6-yl)-1,3-dimethyl-1H-pyrazol-5-ol (3.1 g, 6.08 mmol) was dissolved in toluene (50 mL), cooled to 0 °C, and CMBP (5.9 g, 24.33 mmol) was added. The mixture was then heated to 100 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was slurried with methanol, filtered, and the filter residue was dried to obtain (S)-N 1(4) ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 5 -Nitro-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 α-amine (yellow solid, 1.7 g, 57.3%). MS (ESI) + m / z = 492.3[M+H] + .

[0552] Step 4: (S)-N 1(4) ,24 ,3 1 ,3 3 ,8,9-Hexamethyl-1 5 -Nitro-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 -Amine (600.0 mg, 1.22 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, and 4,4'-bipyridine (38.1 mg, 0.24 mmol) and tetrahydroxydiboron (547.1 mg, 6.10 mmol) were added in portions. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, the mixture was allowed to return to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-N 1(4) ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 ,1 5 2-Diamine (yellow oily substance, 660 mg, crude product). MS (ESI) + m / z = 462.3[M+H] + .

[0553] Preparation of intermediates E17-E33.

[0554] Intermediates E17-E33 were prepared from intermediates C4-C5, C11, C17, C25, C45-C46, C54 and intermediates D11-D14, D18-D23, D25, following the same method used to synthesize intermediate E16. The reaction conditions for the first step were: Pd(OAc)2, CataXCium A, B2pin2, Cs2CO3, 1,4-dioxane, H2O, 100℃; the reaction conditions for the fourth step were: Pd / C, H2, THF, room temperature. See Table 5 for details.

[0555] Table 5. Raw materials, structure, and characterization data of intermediates E17-E33

[0556] Intermediate E35.(S,Z)-N 1(4) ,24 7,8-Tetramethyl-2 1 H,3 1 H-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,1)-imidazolium cyclooctane-1 4 ,1 5 Preparation of -diamine

[0557] Step 1: Using intermediates D7 and C25 as raw materials, prepare (S)-N according to the method in step 1 of the synthesis of intermediate E1. 2 -(5-(tert-butyldimethylsiloxy)pent-2-yl)-N 2 N 4 -Dimethyl-6-(4-methyl-6-(1-triyl-1H-imidazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-nitropyridine-2,4-diamine (yellow solid, 1 g, 76.7%). MS (ESI) + m / z = 822.4[M+H] + .

[0558] Step 2: (S)-N 2 -(5-(tert-butyldimethylsiloxy)pent-2-yl)-N 2 N 4 -Dimethyl-6-(4-methyl-6-(1-triyl-1H-imidazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-nitropyridine-2,4-diamine (1.2 g, 1.5 mmol) was dissolved in ethanol (3 mL), cooled to 0 °C, and a hydrochloric acid ethanol solution (4 M, 1 mL, 4 mmol) was added. The mixture was then heated to 25 °C and stirred for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The resulting residue was adjusted to pH 8 with saturated sodium bicarbonate (5 mL). The mixture was extracted with dichloromethane / methanol (v / v = 20 / 1, 10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-4-((6-(6-(1H-imidazol-4-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(methylamino)-3-nitropyridin-2-yl)(methyl)amino)pentan-1-ol hydrochloride (yellow solid, 500 mg, 68.4%). MS (ESI) + m / z = 466.3 [M+H] + .

[0559] Step 3: Under nitrogen protection, (S)-4-((6-(6-(1H-imidazol-4-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(methylamino)-3-nitropyridin-2-yl)(methyl)amino)pentan-1-ol hydrochloride (300 mg, 0.64 mmol) was dissolved in toluene (5 mL), and TMAD (1.3 g, 6.45 mmol) and tri-n-butylphosphine (1.1 g, 6.45 mmol) were added. The mixture was heated to 60 °C and stirred for 16 h. After the reaction was complete and cooled to room temperature, water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by separation using a C18 reversed-phase column with acetonitrile / water (0.1% formic acid) as the eluent to obtain (7S)-N 1(4) ,2 4 ,7,8-Tetramethyl-1 5 -Nitro-2 1 H,3 1 H-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,1)-imidazolium cyclooctane-1 4 -Amine (yellow solid, 30 mg, 10.8%). MS (ESI) + m / z = 448.3 [M+H] + .

[0560] Step 4: Using (7S)-N 1(4) ,2 4 ,7,8-Tetramethyl-1 5 -Nitro-2 1 H,3 1 H-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,1)-imidazolium cyclooctane-1 4 (S,Z)-N was prepared from amine as a starting material following the method in step four of the synthesis of intermediate E16. 1(4) ,2 4 7,8-Tetramethyl-2 1 H,3 1 H-8-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,1)-imidazolium cyclooctane-1 4 ,1 5 -Diamine, after complete reaction, is used directly in the next reaction without purification. MS(ESI) + m / z = 418.2[M+H] + .

[0561] Intermediate E36.N 3(4),1 1 ,1 3 ,2 4 -Tetramethyl-1 1 H,2 1 H-8-oxa-2(6,1)-pyrazolo[4,3-c]pyridine-3(2,6)-pyridine-1(4,5)-pyrazole-4(1,2)-pyrrolocyclooctane-3 4 ,3 5 Preparation of -diamine

[0562] Step 1: Using intermediate C15 as a starting material, 3-(1-(6-chloro-4-(methylamino)-3-nitropyridin-2-yl)pyrrolidine-2-yl)prop-1-ol (yellow oil, 250 mg, 97.4%) was prepared according to the method described in Step 2 of the synthesis of intermediate E1. MS (ESI) + m / z = 315.0 [M+H] + .

[0563] Step 2: Using 3-(1-(6-chloro-4-(methylamino)-3-nitropyridin-2-yl)pyrrolidine-2-yl)prop-1-ol and 1,3-dimethyl-4-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-5-ol as starting materials, 6-chloro-2-(2-(3-(1,3-dimethyl-4-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)pyrrolidine-1-yl)-N-methyl-3-nitropyridin-4-amine (brown oil, 1.2 g, crude product) was prepared according to the method of step 3 of the synthesis intermediate E16. MS(ESI) + m / z = 624.2[M+H] + .

[0564] Step 3: Under nitrogen protection, 1.2 g of crude 6-chloro-2-(2-(3-(1,3-dimethyl-4-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)pyrrolidine-1-yl)-N-methyl-3-nitropyridine-4-amine was dissolved in a 1,4-dioxane solution of hydrochloric acid (4M, 6 mL) and stirred at 25°C for 6 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give 6-chloro-2-(2-(3-(1,3-dimethyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)pyrrolidine-1-yl)-N-methyl-3-nitropyridine-4-amine (yellow solid, 50 mg, two-step yield: 48.6%). MS (ESI) + m / z = 540.1 [M+H] + .

[0565] Step 4: Under nitrogen protection, 6-chloro-2-(2-(3-(1,3-dimethyl-4-(4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)pyrrolidine-1-yl)-N-methyl-3-nitropyridine-4-amine (300 mg, 0.55 mmol) was dissolved in DMF (6 mL), and potassium carbonate (230.0 mg, 1.66 mmol) was added. 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 water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-10 / 1) to obtain N. 3(4) ,1 1 ,1 3 ,2 4 -Tetramethyl-3 5 -nitro-1 1 H,2 1 H-8-oxa-2(6,1)-pyrazolo[4,3-c]pyridine-3(2,6)-pyridine-1(4,5)-pyrazole-4(1,2)-pyrrolocyclooctane-3 4 -Amine (yellow solid, 200 mg, 71.5%). MS (ESI) + m / z = 504.1 [M+H] + .

[0566] Step 5: Using N 3(4) ,1 1 ,1 3 ,2 4-Tetramethyl-3 5 -nitro-1 1 H,2 1 H-8-oxa-2(6,1)-pyrazolo[4,3-c]pyridine-3(2,6)-pyridine-1(4,5)-pyrazole-4(1,2)-pyrrolocyclooctane-3 4 Using amines as raw materials, N is prepared according to the method in step four of the synthesis of intermediate E16. 3(4) ,1 1 ,1 3 ,2 4 -Tetramethyl-1 1 H,2 1 H-8-oxa-2(6,1)-pyrazolo[4,3-c]pyridine-3(2,6)-pyridine-1(4,5)-pyrazole-4(1,2)-pyrrolidinecyclooctane-3 4 ,3 5 2-Diamine (yellow solid, 80 mg, 85.1%). MS (ESI) + m / z = 474.1 [M+H] + .

[0567] Intermediate E37.(S)-N 3(4) ,2 4 4,5-Tetramethyl-2 1 H-8-oxa-4-aza-2(6,1)-pyrazolo[4,3-c]pyridine-1(5,4)-pyrimidine-3(2,6)-pyridinecyclooctane-3 4 ,3 5 Preparation of -diamine

[0568] Step 1: Using intermediates C4 and D4 as raw materials, prepare (S)-N according to the method in Step 1 of the synthesis of final product 1. 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-)6-(4-methoxypyrimidin-5-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-N 2 -,N 4 -Dimethyl-3-nitropyridine-2,4-diamine (yellow solid, 1.2 g, 66.7%). MS (ESI) + m / z = 608.4 [M+H] + .

[0569] Step 2: (S)-N 2 -(4-(tert-butyldimethylsiloxy)but-2-yl)-6-)6-(4-methoxypyrimidin-5-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-N 2 N 4Dimethyl-3-nitropyridine-2,4-diamine (1.5 g, 0.33 mmol) was dissolved in THF (2 mL), and hydrochloric acid aqueous solution (1 M, 2 mL) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give (S)-5-(1-(6-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridine-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidin-4-ol (yellow solid, 1.3 g, crude product). MS (ESI) + m / z = 480.2[M+H] + .

[0570] Steps 3 and 4: Using (S)-5-(1-(6-((4-hydroxybut-2-yl)(methyl)amino)-4-(methylamino)-5-nitropyridin-2-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidin-4-ol as a starting material, (S)-N was prepared according to the methods in steps 4 and 5 of the synthesis intermediate E1. 3(4) ,2 4 4,5-Tetramethyl-2 1 H-8-oxa-4-aza-2(6,1)-pyrazolo[4,3-c]pyridine-1(5,4)-pyrimidine-3(2,6)-pyridinecyclooctane-3 4 ,3 5 2-Diamine (yellow solid, 400 mg, 85%). MS (ESI) + m / z = 432.0 [M+H] + .

[0571] Intermediate E38.(S)-N 1(4) ,3 1 ,8,9-Tetramethyl-2 4 -Vinyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 ,1 5 Preparation of -diamine

[0572] Step 1: (S)-2 4 ,3 1 ,8,9-Tetramethyl-1 4 -(methylamino)-1 5 -Nitro-2 1 H,3 1H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 -Amine (the product obtained in step 3 of the preparation of intermediate E20) (500 mg, 1.05 mmol) was dissolved in 1,4-dioxane (10 mL), and selenium dioxide (174 mg, 1.57 mmol) was added. The mixture was heated to 100 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed successively with water (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using dichloromethane / methanol (20 / 1) as the developing solvent to obtain (S)-3. 1 ,8,9-Trimethyl-1 4 -(methylamino)-1 5 -Nitro-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-2 4 - Formaldehyde (yellow solid, 300 mg, 58.3%). MS (ESI) + m / z = 492.1 [M+H] + .

[0573] Step 2: Dissolve methyltriphenylphosphine iodide (185 mg, 0.46 mol) in tetrahydrofuran (10 mL), add potassium tert-butoxide (68.4 mg, 0.61 mol), stir at 25 °C for 1 h, and add (S)-3 dropwise. 1 ,8,9-Trimethyl-1 4 -(methylamino)-1 5 -Nitro-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-2 4 A solution of formaldehyde (150 mg, 0.31 mol) in tetrahydrofuran (5 mL) was stirred at 25 °C for 1 h. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using dichloromethane / methanol (20 / 1) as the developing solvent to obtain (S)-N 1(4) ,3 1 ,8,9-Tetramethyl-15 -Nitro-2 4 -Vinyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 -Amine (yellow solid, 50 mg, 33.4%). MS (ESI) + m / z = 490.3[M+H] + .

[0574] Step 3: Using (S)-N 1(4) ,3 1 ,8,9-Tetramethyl-1 5 -Nitro-2 4 -Vinyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 (S)-N was prepared from amine as a starting material, following the method in step four of the synthesis intermediate E16. 1(4) ,3 1 ,8,9-Tetramethyl-2 4 -Vinyl-2 1 H,3 1 H-4-oxa-9-aza-2(1,6)-pyrazolo[4,3-c]pyridine-1(2,6)-pyridine-3(4,5)-pyrazolcyclononane-1 4 ,1 5 2-Diamine (yellow solid, 50 mg, crude product). MS (ESI) + m / z = 460.2[M+H] + .

[0575] Preparation of intermediates F1-F52 in the sixth preparation example

[0576] Preparation of intermediate F1.N-(dichloromethylene)-N-methyl-2-methoxyethyl-1-ammonium chloride

[0577] Step 1: Dissolve 2-methoxy-N-methylethylamine (3.0 g, 33.65 mmol) in a mixture of ethanol (40 mL) and water (10 mL), cool to 0 °C, slowly add carbon disulfide (4.1 g, 53.85 mmol), and heat to room temperature with stirring for 2 h. Then slowly add iodomethane (5.7 g, 40.39 mmol), and stir at room temperature for 4 h. After the reaction is complete, concentrate the reaction solution under reduced pressure, extract with dichloromethane (40 mL × 3), combine the organic phases and wash with saturated brine (40 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain methyl (2-methoxyethyl)(methyl)aminodithiocarbamate (yellow oil, 2 g, 31.6%). MS (ESI) + m / z = 180.0 [M+H] + .

[0578] Step 2: Methyl (2-methoxyethyl)(methyl)aminodithiocarbamate (1.0 g, 5.58 mmol) was dissolved in dichloromethane (20 mL), cooled to 10 °C to displace chlorine gas, and then heated to room temperature with stirring for 2 h. After the reaction was complete, dichloromethane was removed to obtain N-(dichloromethylene)-N-methyl-2-methoxyethyl-1-ammonium chloride (white solid, 1 g, crude product). This was used directly in the next reaction without purification.

[0579] Preparation of intermediates F2-F33

[0580] Intermediates F2-F33 were prepared using commercially available amine compounds as raw materials and the method for synthesizing intermediate F1. See Table 6 for details.

[0581] Table 6. Structure of intermediates F2-F33

[0582] Preparation of intermediate F34. 1-(dichloromethylene)-4-(trifluoromethyl)piperazine-1-ammonium chloride

[0583] Step 1: Under nitrogen protection, tert-butyl piperazine-1-carboxylate (10 g, 53.4 mmol) was dissolved in acetonitrile (100 mL), followed by the sequential addition of carbon disulfide (4.07 g, 53.4 mmol), silver fluoride (33.87 g, 0.27 mol), and triethylenediamine (2.99 g, 26.7 mmol). The mixture was heated to 80 °C and stirred for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (50 / 1-20 / 1) to obtain tert-butyl 4-(trifluoromethyl)piperazine-1-carboxylate (yellow solid, 2 g, 14.61%).

[0584] Step 2: Dissolve tert-butyl 4-(trifluoromethyl)piperazine-1-carboxylate (2 g, 7.84 mmol) in a 1,4-dioxane solution of hydrochloric acid (4 M, 20 mL) and stir at 25 °C for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain 1-(trifluoromethyl)piperazine hydrochloride (yellow solid, 1.5 g, crude product). MS (ESI) + m / z = 155.1 [M+H] + .

[0585] Step 3: Under nitrogen protection, 1-(trifluoromethyl)piperazine hydrochloride (1.5 g, 7.87 mmol) and triethylamine (796 mg, 7.87 mmol) were dissolved in a mixed solution of ethanol / water (v / v = 4 / 1, 30 mL), cooled to 0 °C, and carbon disulfide (958.77 mg, 12.59 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h, and iodomethane (1.34 g, 9.44 mmol) was added dropwise at 0 °C. The mixture was then heated to 25 °C and stirred for 14 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was extracted with dichloromethane (50 mL × 3), the organic phases were combined and washed with saturated brine, 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 dichloromethane / methanol (50 / 1-10 / 1) to obtain methyl 4-(trifluoromethyl)piperazine-1-dithiocarbamate (yellow solid, 300 mg, 15.6%). MS (ESI) + m / z = 245.1 [M+H] + .

[0586] Step 4: Using methyl 4-(trifluoromethyl)piperazine-1-dithiocarbamate as a raw material, prepare 1-(dichloromethylene)-4-(trifluoromethyl)piperazine-1-ammonium chloride (yellow solid, 400 mg, crude product) according to the method in step 2 of the synthesis intermediate F1.

[0587] Preparation of intermediate F35. 2-(dichloromethylene)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-ammonium chloride

[0588] Step 1: Using tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate and formaldehyde aqueous solution as raw materials, tert-butyl 5-methyl-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (white solid, 10g, crude product) was prepared according to the method in step 3 of the synthesis of intermediate A6.

[0589] Steps 2 to 4: Using 5-methyl-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester as raw material, 2-(dichloromethylene)-5-methyl-2,5-diazabicyclo[2.2.2]octane-2-ammonium chloride (yellow solid, 200 mg, crude product) was prepared according to the method of steps 2 to 4 of the synthesis intermediate F34.

[0590] Preparation of intermediate F36, 1-(dichloromethylene)-4-(dimethylamino)-3,3-difluoropiperidine-1-ammonium chloride

[0591] Using tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate as a raw material, 1-(dichloromethylene)-4-(dimethylamino)-3,3-difluoropiperidine-1-ammonium chloride (yellow solid, 200 mg, crude product) was prepared according to the method for synthesizing intermediate F35.

[0592] Preparation of intermediate F37. 1-(dichloromethylene)-4-(difluoromethoxy)piperidine-1-ammonium chloride

[0593] Step 1: Under nitrogen protection, dissolve 12 g (51.0 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate in 100 mL of acetonitrile, add cuprous iodide (1.94 g, 10.2 mmol), heat to 45 °C, add dropwise a solution of methyl fluorosulfonyl difluoroacetate (13.6 g, 76.5 mmol) in 100 mL of acetonitrile, and stir at 50 °C for 1 h. After the reaction was complete and cooled to room temperature, saturated sodium bicarbonate (200 mL) solution was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1) to obtain benzyl 4-(difluoromethoxy)piperidine-1-carboxylate (yellow oil, 5.5 g, 37.8%). MS (ESI) + m / z = 286.0 [M+H] + .

[0594] Step 2: Under nitrogen protection, 4-(difluoromethoxy)piperidine-1-carboxylic acid benzyl ester (5 g, 17.5 mmol) was dissolved in methanol (50 mL), and 10% Pd / C (5.59 g, 52.5 mmol) was added to replace the hydrogen gas. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(difluoromethoxy)piperidine (yellow oil, 3.5 g, crude product). MS (ESI) + m / z = 152.1 [M+H] + .

[0595] Steps 3 and 4: Using 4-(difluoromethoxy)piperidine as a raw material, 1-(dichloromethylene)-4-(difluoromethoxy)piperidine-1-ammonium chloride (yellow solid, 1.0 g, crude product) was prepared according to the method for synthesizing intermediate F1.

[0596] Preparation of intermediate F38, 1-(dichloromethylene)-3-(difluoromethyl)-4-methylpiperazine-1-ammonium chloride

[0597] Step 1: Using 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylate and formaldehyde aqueous solution as raw materials, 1-(tert-butyl)-3-methyl-4-methylpiperazine-1,3-dicarboxylate (yellow oil, 16 g, 75.6%) was prepared according to the method in step 3 of the synthesis of intermediate A6. MS (ESI) + m / z = 259.2[M+H] + .

[0598] Step 2: Under nitrogen protection, 1-(tert-butyl)-3-methyl-4-methylpiperazine-1,3-dicarboxylate (22 g, 85.2 mmol) was dissolved in toluene (220 mL), cooled to -78 °C, and DIBAL-H toluene solution (1 M, 170.3 mL, 170.3 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 h. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (50 / 1-20 / 1) to obtain tert-butyl 3-formyl-4-methylpiperazine-1-carboxylate (yellow oil, 4.0 g, 20.6%).

[0599] Step 3: Under nitrogen protection, tert-butyl 3-formyl-4-methylpiperazine-1-carboxylate (3g, 13.1mmol) was dissolved in dichloromethane (30mL), cooled to -78℃, and a dichloromethane (40mL) solution of DAST (4.22g, 26.28mmol) was added dropwise. The mixture was stirred at -78℃ for 1h, and then heated to 25℃ and stirred for 6h. After the reaction was complete, saturated sodium bicarbonate (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-50 / 1) to obtain tert-butyl 3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (yellow oil, 1.7 g, 51.7%). MS (ESI) + m / z = 251.3[M+H] + .

[0600] Step 4: Under nitrogen protection, tert-butyl 3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (1.5 g, 5.99 mmol) was dissolved in dichloromethane (15 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 3 mL) was added dropwise. The mixture was stirred at 25 °C for 3 h. After the reaction was complete, the mixture was filtered, and the residue was collected and dried to obtain 2-(difluoromethyl)-1-methylpiperazine hydrochloride (yellow solid, 0.9 g, 80.5%). MS (ESI) + m / z = 151.2[M+H] + .

[0601] Steps 5 and 6: Using 2-(difluoromethyl)-1-methylpiperazine hydrochloride as raw material, 1-(dichloromethylene)-3-(difluoromethyl)-4-methylpiperazine-1-ammonium chloride (yellow solid, 310 mg, crude product) was prepared according to the methods in steps 3 and 4 of the synthesis of intermediate F34.

[0602] Preparation of intermediate F39. 1-(dichloromethylene)-6,6-difluoro-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-ammonium chloride

[0603] Step 1: Dissolve tert-butyl 6,6-difluoro-1,4-diazacycloheptane-1-carboxylate (900 mg, 3.8 mmol) and triethylamine (577 mg, 5.7 mmol) in DCM (10 mL), cool to 0 °C, add trifluoroacetic anhydride (960 mg, 4.57 mmol) dropwise, heat to 25 °C and stir for 16 h. After the reaction is complete, add water (10 mL) to the reaction solution, extract the mixture with dichloromethane (30 mL), combine the organic phases and wash with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with a gradient elution of petroleum ether / ethyl acetate (10 / 1-2 / 1) to obtain tert-butyl 6,6-difluoro-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-carboxylate (yellow oil, 1.2 g, 95.2%). MS(ESI + m / z = 277.0 [M-56+H] + .

[0604] Steps 2 to 4: Using tert-butyl 6,6-difluoro-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-carboxylate as the raw material, 1-(dichloromethylene)-6,6-difluoro-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-ammonium chloride (yellow solid, 500 mg, crude product) was prepared sequentially according to the methods of Step 3 of intermediate C54 and Step 3 and Step 4 of intermediate F34.

[0605] Preparation of intermediate F40. 1-(dichloromethylene)-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-ammonium chloride

[0606] Using tert-butyl 1,4-diaza-1-carboxylate as a raw material, 1-(dichloromethylene)-4-(2,2,2-trifluoroacetyl)-1,4-diazacycloheptane-1-ammonium chloride (yellow solid, 1g, crude product) was prepared according to the method of synthesizing intermediate F39.

[0607] Preparation of intermediate F41. 5-(dichloromethylene)-2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-ammonium chloride

[0608] Step 1: Under nitrogen protection, 1-benzylpiperidin-4-one (50g, 0.26mol) was dissolved in tetrahydrofuran (500mL), cooled to -78℃, and LDA (2M, 198mL, 0.40mmol) was slowly added dropwise. The mixture was stirred at -78℃ for 1h, and then ethyl bromoacetate (66.18g, 0.40mol) was added dropwise. The mixture was stirred at -78℃ for 3h. After the reaction was complete, saturated ammonium chloride (500 mL) solution was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water (200 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (5 / 1-2 / 1) to obtain 2-(1-benzyl-4-oxopiperidin-3-yl)ethyl acetate (yellow oil, 26.0 g, 35.7%). MS (ESI) + m / z = 276.3 [M+H] + .

[0609] Step 2: Under nitrogen protection, ethyl 2-(1-benzyl-4-oxopiperidin-3-yl)acetate (20.5 g, 0.07 mol) was dissolved in methanol (300 mL), and ammonium acetate (57.39 g, 0.74 mol) and sodium cyanoborohydride (3.27 g, 0.05 mmol) were added sequentially. The mixture was stirred at 25 °C for 6 h, and then heated to 60 °C and stirred for 24 h. After the reaction was complete and cooled to room temperature, water (500 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (80 / 1-30 / 1) to obtain 5-benzyloctahydro-2H-pyrrolo[3,2-c]pyridin-2-one (yellow oil, 5.0 g, 29.1%). MS (ESI) + m / z = 231.1[M+H] + .

[0610] Step 3: Under nitrogen protection, 5-benzyloctahydro-2H-pyrrolo[3,2-c]pyridin-2-one (4.0 g, 17.37 mmol) was dissolved in ethanol (50 mL), and 10% Pd / C (3.68 g, 34.73 mmol) was added to replace the hydrogen gas. The mixture was heated to 50 °C and stirred for 24 h. After the reaction was complete, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain octahydro-2H-pyrrolo[3,2-c]pyridin-2-one (yellow oil, 2.4 g, 98.7%). MS (ESI) + m / z = 141.1 [M+H] + .

[0611] Steps 4 and 5: Using octahydro-2H-pyrrolo[3,2-c]pyridin-2-one as the raw material, prepare 5-(dichloromethylene)-2-oxooctahydro-1H-pyrrolo[3,2-c]pyridin-5-ammonium chloride (yellow solid, 500 mg, crude product) according to the method of steps 3 and 4 of the synthesis intermediate F34.

[0612] Preparation of intermediate F42. 2-(dichloromethylene)-5-methyl-4-oxooctahydropyrrolo[3,4-c]pyrrole-2-ammonium chloride

[0613] Step 1: Dissolve tert-butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4 g, 21.8 mmol) in dichloromethane (100 mL), add N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (5.2 g, 21.8 mmol) and trifluoroacetic acid (0.25 g, 2.2 mmol), and stir at 25 °C for 16 h. After the reaction was complete, 100 mL of sodium bicarbonate aqueous solution was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (10 / 1-5 / 1) to obtain tert-butyl 5-benzyl-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (yellow oil, 5 g, 72.5%). MS (ESI) + m / z = 317.1 [M+H] + .

[0614] Step 2: Using tert-butyl 5-benzyl-1-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as the starting material, 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1(2H)-one (yellow oil, 3g, 87.9%) was prepared according to the method in Step 3 of the synthesis of intermediate C54. MS (ESI) + m / z = 217.2[M+H] + .

[0615] Step 3: Under nitrogen protection, 2 g (9.26 mmol) of 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1(2H)-one was dissolved in DMF (20 mL), sodium hydride (554.8 mg, 13.9 mmol) was added, and the mixture was stirred at 25 °C for 1 h. Iodomethane (1.3 g, 9.26 mmol) was added, and the mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (20 / 1-10 / 1) to obtain 5-benzyl-2-methylhexahydropyrrolo[3,4-c]pyrrole-1(2H)-one (yellow oil, 500 mg, 23.8%). MS(ESI + m / z = 231.2[M+H] + .

[0616] Steps 4 to 6: Using 5-benzyl-2-methylhexahydropyrrolo[3,4-c]pyrrole-1(2H)-one as the starting material, 2-(dichloromethylene)-5-methyl-4-oxooctahydropyrrolo[3,4-c]pyrrole-2-ammonium chloride (yellow solid, 250 mg, crude product) was prepared according to the method of steps 3 to 5 of synthetic intermediate F41.

[0617] Preparation of intermediate F43. 2-(dichloromethylene)-7-oxooctahydro-1H-pyrrolo[1,2-a][1,4]diazaphen-2-ammonium chloride

[0618] Step 1: Under nitrogen protection, 5-(hydroxymethyl)pyrrolidone-2-one (5 g, 3.43 mmol) was dissolved in dichloromethane (50 mL), and TEA (13.16 g, 130.28 mmol) and MsCl (7.46 g, 65.14 mmol) were added. The mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl (5-oxopyrrolidone-2-yl)methanesulfonate (yellow oil, 2.5 g, 29.8%). MS (ESI) + m / z = 194.1 [M+H] + .

[0619] Step 2: Under nitrogen protection, methyl (5-oxopyrrolidone-2-yl)methanesulfonate (2.3 g, 11.9 mmol) and N-benzyl-3-aminopropanol (6.88 g, 41.66 mmol) were mixed and heated to 50 °C with stirring for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and water (30 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (50 mL × 3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-50 / 1) to obtain 5-((benzyl(3-hydroxypropyl)amino)methyl)pyrrolidone-2-one (yellow oil, 1.5 g, 48.0%). MS (ESI) + m / z = 263.2[M+H] + .

[0620] Step 3: Using 5-((benzyl(3-hydroxypropyl)amino)methyl)pyrrolidone-2-one as the starting material, prepare 3-(benzyl((5-oxopyrrolidone-2-yl)methyl)amino)propyl methanesulfonate (white solid, 1.5 g, 77%) according to the method in Step 1. MS (ESI) + m / z = 341.2[M+H] + .

[0621] Step 4: Under nitrogen protection, 3-(benzyl((5-oxopyrrolidone-2-yl)methyl)amino)propyl methanesulfonate (1.5 g, 4.41 mmol) was dissolved in THF (15 mL), cooled to 0 °C, and 60% NaH (0.26 g, 6.61 mmol) was added in portions. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, ice water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (100 / 1-50 / 1) to obtain 2-benzyloctahydro-7H-pyrrolo[1,2-a][1,4]diazaphen-7-one (white solid, 0.3 g, 27.9%). MS (ESI) + m / z = 245.1 [M+H] + .

[0622] Steps 5 to 7: Using 2-benzyloctahydro-7H-pyrrolo[1,2-a][1,4]diazaphen-7-one as the starting material, 2-(dichloromethylene)-7-oxooctahydro-1H-pyrrolo[1,2-a][1,4]diazaphen-2-ammonium chloride (white solid, 100 mg, crude product) was prepared according to the method of steps 3 to 5 of synthetic intermediate F41.

[0623] Preparation of intermediate F44. 1-(dichloromethylene)-4-(2-oxopyrrolidone-1-yl)piperidine-1-ammonium chloride

[0624] Step 1: 1-Benzylpiperidin-4-amine (2 g, 10.51 mmol) was dissolved in DMF (20 mL), and methyl 4-bromobutyrate (1.90 g, 10.51 mmol) and potassium carbonate (2.90 g, 21.02 mmol) were added. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (20 / 1-10 / 1) to obtain 1-(1-benzylpiperidin-4-yl)pyrrolidine-2-one (yellow oil, 500 mg, 18.4%). MS (ESI) + m / z = 259.2[M+H] + .

[0625] Steps 2 to 4: Using 1-(1-benzylpiperidin-4-yl)pyrrolidine-2-one as the starting material, 1-(dichloromethylene)-4-(2-oxopyrrolidine-1-yl)piperidin-1-ammonium chloride (yellow solid, 100 mg, crude product) was prepared according to the method of steps 3 to 5 of synthetic intermediate F41.

[0626] Preparation of intermediate F45. 4-acetamido-1-(dichloromethylene)piperidine-1-ammonium chloride

[0627] Step 1: Dissolve 10 g (0.04 mol) of 3,3-dibromo-1,1,1-trifluoroprop-2-one in 100 mL of water, add sodium acetate (33.46 g, 0.41 mol), and heat to 100 °C with stirring for 12 h. After the reaction is complete, cool to room temperature, extract the reaction solution with ethyl acetate (50 mL), combine the organic phases and wash with saturated brine (200 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, dissolve the residue in methanol (100 mL), and add N2O2 sequentially. 11,2-benzylethane-1,2-diamine (16.8 g, 0.11 mol) and sodium cyanoborocyanate (4.66 g, 0.07 mol) were reacted and heated to 60 °C with stirring for 16 h. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of dichloromethane / methanol (50 / 1-20 / 1) to obtain 1-benzyl-3-(trifluoromethyl)piperazine (yellow oil, 0.58 g, 6.4%). MS (ESI) + m / z = 245.3[M+H] + .

[0628] Step 2: Using 1-benzyl-3-(trifluoromethyl)piperazine as a starting material, 4-benzyl-1-methyl-2-(trifluoromethyl)piperazine (yellow oil, 1.2 g, crude product) was prepared according to the method in Step 3 of the synthesis of intermediate A6. MS (ESI) + m / z = 259.2[M+H] + .

[0629] Step 3: Under nitrogen protection, 4-benzyl-1-methyl-2-(trifluoromethyl)piperazine (1.1 g, 4.26 mmol) was dissolved in methanol (20 mL), and 10% Pd / C (1.35 g, 1.28 mmol) and acetic acid (2 mL) were added to displace hydrogen. The mixture was heated to 50 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-methyl-2-(trifluoromethyl)piperazine (yellow solid, 0.8 g, crude product). MS (ESI) + m / z = 169.2 [M+H] + .

[0630] Steps 4 and 5: Using 1-methyl-2-(trifluoromethyl)piperazine as raw material, prepare 4-acetamido-1-(dichloromethylene)piperidine-1-ammonium chloride (yellow solid, 200 mg, crude product) according to the method for synthesizing intermediate F1.

[0631] Preparation of intermediate F46, 1-(dichloromethylene)-3-(fluoromethyl)-4-methylpiperazine-1-ammonium chloride

[0632] Step 1: Using tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate and formaldehyde as raw materials, tert-butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (yellow oil, 3g, 28.2%) was prepared according to the method in step 3 of the synthesis of intermediate A6. MS (ESI) + m / z = 231.3[M+H] +.

[0633] Step 2: Dissolve 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (3 g, 13.02 mmol) in DCM (50 mL), cool to 0 °C, add DAST (2.52 g, 15.63 mmol) dropwise, heat to 45 °C and stir for 16 h. After the reaction is complete, cool to room temperature, add saturated sodium bicarbonate solution (50 mL), extract the mixture with dichloromethane (20 mL × 3), combine the organic phases and wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-10 / 1) to obtain 3-(fluoromethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (yellow solid, 3 g, 99%). MS (ESI) + m / z = 233.3[M+H] + .

[0634] Steps 3 to 5: Using tert-butyl 3-(fluoromethyl)-4-methylpiperazine-1-carboxylate as the raw material, 1-(dichloromethylene)-3-(fluoromethyl)-4-methylpiperazine-1-ammonium chloride (yellow solid, 900 mg, crude product) was prepared according to the method of steps 4 to 6 of the synthesis intermediate F38.

[0635] Preparation of intermediate F47. 1-(dichloromethylene)-3-(methoxycarbonyl)-4-methylpiperazine-1-ammonium chloride

[0636] Using 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylate and formaldehyde as raw materials, 1-(dichloromethylene)-3-(methoxycarbonyl)-4-methylpiperazine-1-ammonium chloride (yellow solid, 720 mg, crude product) was prepared according to the method of synthesizing intermediate F35.

[0637] Preparation of intermediate F48. 5-(dichloromethylene)-1-methyl-2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-ammonium chloride

[0638] Step 1: Using methyl 2-oxooctahydro-5H-pyrrolo[3,2-c]pyridine-5-dithiocarbamate as a starting material, methyl 1-methyl-2-oxooctahydro-5H-pyrrolo[3,2-c]pyridine-5-dithiocarbamate (yellow solid, 160 mg, 75.5%) was prepared according to the method in step 3 of the synthesis of intermediate F42. MS (ESI) + m / z = 245.1 [M+H] + .

[0639] Step 2: Using methyl 1-methyl-2-oxooctahydro-5H-pyrrolo[3,2-c]pyridine-5-dithiocarbamate as the raw material, 5-(dichloromethylene)-1-methyl-2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-ammonium chloride (yellow solid, 150 mg, crude product) was prepared according to the method of Step 2 of the synthesis intermediate F1.

[0640] Preparation of intermediate F49. 2-(dichloromethylene)-5-(2,2,2-trifluoroacetyl)octahydropyrrolo[3,4-c]pyrrole-2-ammonium chloride

[0641] Step 1: Using hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate tert-butyl ester as the starting material, 5-(2,2,2-trifluoroacetyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate tert-butyl ester (yellow solid, 5.0 g, 98.3%) was prepared according to the method in Step 1 of the synthesis intermediate F39. MS (ESI) + m / z = 253.2[M+H] + .

[0642] Step 2: Using tert-butyl 5-(2,2,2-trifluoroacetyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate as the starting material, 2,2,2-trifluoro-1-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one trifluoroacetate (yellow solid, 8 g, crude product) was prepared according to the method in Step 3 of the synthesis intermediate C54. MS(ESI) + m / z = 209.1 [M+H] + .

[0643] Steps 3 and 4: Using 2,2,2-trifluoro-1-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one trifluoroacetate as a raw material, 2-(dichloromethylene)-5-(2,2,2-trifluoroacetyl)octahydropyrrolo[3,4-c]pyrrolo-2-ammonium chloride (yellow solid, 300 mg, crude product) was prepared according to the method of synthesizing intermediate F1.

[0644] Preparation of intermediate F50. 3-Bromo-7-(dichloromethylene)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-ammonium chloride

[0645] Step 1: Using 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine as a starting material, methyl 5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-dithiocarbamate (yellow solid, 2.7 g, 78.0%) was prepared according to the method described in Step 1 of the synthesis of intermediate F1. MS (ESI) +m / z = 214.1[M+H] + .

[0646] Step 2: Using methyl 5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-dithiocarbamate as a starting material, methyl 3-bromo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-dithiocarbamate (yellow solid, 400 mg, 10.8%) was prepared according to the method described in Step 2 of the synthesis of intermediate D24. MS (ESI) + m / z = 291.9 / 293.9 [M+H] + .

[0647] Step 3: Using methyl 3-bromo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-dithiocarbamate as a raw material, 3-bromo-7-(dichloromethylene)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-ammonium chloride (yellow solid, 500 mg, crude product) was prepared according to the method in step 2 of the synthesis intermediate F1.

[0648] Preparation of intermediate F51. 3-bromo-5-(dichloromethylene)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-ammonium chloride

[0649] Step 1: Using 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl formate as the starting material, 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine trifluoroacetate (yellow oil, 1 g, crude product) was prepared according to the method in step 3 of the synthesis intermediate C54. MS (ESI) + m / z = 291.9 [M+H] + .

[0650] Steps 2 and 3: Using 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine trifluoroacetate as a raw material, 3-bromo-5-(dichloromethylene)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-ammonium chloride (white solid, 200 mg, crude product) was prepared according to the method for synthesizing intermediate F1.

[0651] Preparation of intermediate F52. 3-bromo-7-(dichloromethylene)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-ammonium chloride

[0652] Using tert-butyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate as a raw material, 3-bromo-7-(dichloromethylene)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-ammonium chloride (yellow solid, 500 mg, crude product) was prepared according to the method of synthesizing intermediate F51.

[0653] Preparation of intermediates G1-G10 in the seventh preparation example

[0654] Preparation of intermediate G1. tert-butyl 1-carboxylate, azacyclobutane-1-carboxylate

[0655] 1.2 g (6.97 mmol) of tert-butyl 3-aminoazacyclobutane-1-carboxylate was dissolved in DCM (24 mL), cooled to 0 °C, and TEA (1.5 g, 14.84 mmol) was added sequentially, followed by dropwise addition of phosgene (1.6 g, 13.93 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, 20 mL of saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with dichloromethane (20 mL × 2), the organic phases were combined and washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-isothiocyanate azacyclobutane-1-carboxylate (brown oil, 1.5 g, crude product).

[0656] Preparation of intermediate G2,3-isothiocyanate tetrahydrofuran

[0657] Tetrahydrofuran-3-amine hydrochloride (100.0 mg, 0.81 mmol) was dissolved in DMF (1 mL), and 1,1-thiocarbonyldiimidazole (158.6 mg, 0.89 mmol) and triethylamine (245.7 mg, 2.43 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, 3-isothiocyanate tetrahydrofuran (black oil, 105 mg, crude product) was given. It was used directly in the next reaction without purification. MS (ESI) + m / z = 267.0 [M + PMB - NH3] + .

[0658] Preparation of intermediate G3.4-isothiocyanate-1-methyl-1H-pyrazole

[0659] 1-Methyl-1H-pyrazole-4-amine (500.0 mg, 5.15 mmol) was dissolved in toluene (10 mL), and dimethylaminothiocarbamate chloride (668.1 mg, 5.41 mmol) was added. The mixture was heated to 110 °C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 4-isothiocyano-1-methyl-1H-pyrazole (yellow oil, 450 mg, crude product).

[0660] Preparation of intermediate G4. tert-butyl(2-isothiocyanate ethoxy)dimethylsilane

[0661] Step 1: Dissolve 2-aminoethane-1-ol (5.0 g, 81.86 mmol) in DCM (50 mL), cool to 0 °C, and add imidazole (11.1 g, 163.72 mmol) and TBSCl (14.8 g, 98.23 mmol) sequentially. Stir overnight at room temperature. After the reaction is complete, add water (80 mL) to the reaction solution. Extract the mixture with dichloromethane (80 mL × 3), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 10) as eluent to obtain 2-(tert-butyldimethylsiloxy)ethyl-1-amine (yellow oil, 6 g, 40.4%).

[0662] Step 2: 2-(tert-butyldimethylsiloxy)ethyl-1-amine (2.0 g, 11.41 mmol) was dissolved in 1,4-dioxane (20 mL), and 1,1-thiocarbonyldiimidazole (2.2 g, 12.55 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, tert-butyl(2-isothiocyanate ethoxy)dimethylsilane was obtained. It was used directly in the next reaction without purification. MS (ESI) + m / z = 355.2[M + PMB - NH3] + .

[0663] Preparation of intermediates G5-G9

[0664] Intermediates G5-G9 were prepared using commercially available amine compounds as raw materials, following the same method used to prepare intermediate G1. See Table 7 for details.

[0665] Table 7. Structure of intermediates G5-G9

[0666] Preparation of intermediate G10. (ethyl isothiocyanate) (methyl)carbamate tert-butyl ester

[0667] Under nitrogen protection, tert-butyl (2-aminoethyl)(methyl)carbamate (2 g, 11.48 mmol) was dissolved in ethanol (30 mL), and carbon disulfide (2.62 g, 34.43 mmol) and triethylamine (1.16 g, 11.48 mmol) were added. The mixture was stirred at 25 °C for 2 h, and then 4-dimethylaminopyridine (0.14 g, 1.15 mmol) and di-tert-butyl dicarbonate (2.50 g, 11.48 mmol) were added. The mixture was reacted at 25 °C for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain tert-butyl (2-ethyl isothiocyanate)(methyl)carbamate (yellow oil, 1.5 g, 60.5%).

[0668] Preparation of intermediates H1-H13 in Group 8

[0669] Preparation of intermediate H1. 4-(chlorocarbonyl)piperidine-1-carboxylic acid benzyl ester

[0670] Under nitrogen protection, 1-benzyloxycarbonylpiperidine-4-carboxylic acid (500 mg, 1.89 mmol) was dissolved in a mixed solution of dichloromethane (4 mL), dimethyl sulfoxide (2 mL), and DMF (0.5 mL), and stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give benzyl 4-(chlorocarbonyl)piperidine-1-carboxylic acid ester (yellow oil, 500 mg, crude product). MS (ESI) + m / z = 367.8 [M+H] + .

[0671] Preparation of intermediate H2-H7

[0672] Intermediates H2-H7 were prepared from commercially available acid compounds using the method for preparing intermediate H1, with reaction temperatures ranging from room temperature to 80°C. See Table 8 for details.

[0673] Table 8. Structure of intermediates H2-H7

[0674] Preparation of intermediate H8.2-(methylaminosulfonyl)acetic acid

[0675] Step 1: Methyl 2-(chlorosulfonyl)acetate (1 g, 5.80 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 5 °C, and methylamine tetrahydrofuran solution (2 M, 6 mL, 11.59 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 4 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (100 / 1-1 / 1) to obtain methyl 2-(sulfonyl)acetate (colorless oil, 340 mg, 58.99%). MS (ESI) + m / z = 166.1 [MH] - .

[0676] Step 2: Methyl 2-(sulfonyl)acetate (340 mg, 2.03 mmol) was dissolved in methanol (5 mL), and a methanol solution of sodium carbonate (520 mg, 4.91 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 3 h. After the reaction was complete, water was added to the reaction solution, and the solution was adjusted to neutral with HCl (2 M, 3 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-(methylaminosulfonyl)acetic acid (white solid, 120 mg, 38.53%). MS (ESI) + m / z = 152.0 [MH] - .

[0677] Preparation of intermediate H9. 3,6-dihydro-2H-pyran-4-carboxylic acid

[0678] Methyl 3,6-dihydro-2H-pyran-4-carboxylate (1.0 g, 7.04 mmol) was dissolved in a mixed solution of tetrahydrofuran (4 mL), ethanol (4 mL), and water (2 mL). Sodium hydroxide (0.88 g, 21.1 mmol) was added, and the mixture was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The resulting residue was adjusted to pH 4-5 with 2 M HCl. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3,6-dihydro-2H-pyran-4-carboxylic acid (white solid, 500 mg, 55.7%).

[0679] Preparation of intermediate H10.2-(3,3-difluoroazacyclobutan-1-yl)acetic acid

[0680] Step 1: Dissolve 3,3-difluoroazacyclobutane hydrochloride (500 mg, 3.86 mmol) in acetonitrile (10 mL), then add potassium carbonate (1.60 g, 11.58 mmol) and benzyl 2-bromoacetate (1.06 g, 4.63 mmol) sequentially. Heat to 50 °C and stir for 16 h. After the reaction is complete, cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain benzyl 2-(3,3-difluoroazacyclobutane-1-yl)acetate (yellow oil, 800 mg, 85.9%).

[0681] Step 2: Under nitrogen protection, benzyl 2-(3,3-difluoroazacyclobutane-1-yl)acetate (800 mg, 3.32 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (352.9 mg, 3.32 mmol) was added to replace the hydrogen gas. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(3,3-difluoroazacyclobutane-1-yl)acetic acid (white solid, 400 mg, 79.8%).

[0682] Preparation of intermediate H11. 3-oxooctahydroindene-7-carboxylic acid

[0683] Step 1: Using methyl 2-bromoisonicotinic acid and ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)acrylate as raw materials, methyl (E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)isonicotinic acid (white solid, 1.8 g, 82.6%) was prepared according to the method in Step 1 of the synthesis of intermediate D17.

[0684] Step 2: Under nitrogen protection, methyl (E)-2-(3-ethoxy-3-oxopropyl-1-en-1-yl)isonicotinic acid (1.3 g, 5.53 mmol) was dissolved in acetic acid (13 mL), and 20% Pd(OH)₂ / C (200 mg, 0.29 mmol) was added to displace hydrogen. The mixture was heated to 50 °C and stirred for 6 h. After the reaction was complete, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-(3-ethoxy-3-oxopropyl)piperidine-4-carboxylate (yellow solid, 1.45 g, crude product). MS (ESI) + m / z = 244.2[M+H] + .

[0685] Step 3: Methyl 2-(3-ethoxy-3-oxopropyl)piperidine-4-carboxylate (600 mg, 2.47 mmol) was dissolved in acetonitrile (10 mL), and TEA (747.2 mg, 7.40 mmol) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using dichloromethane / methanol (50 / 1) as the developing solvent to obtain methyl 3-oxooctahydroindene-7-carboxylate (colorless oil, 400 mg, 82.2%). MS (ESI) + m / z = 198.2[M+H] + .

[0686] Step 4: Methyl 3-oxooctahydroindene-7-carboxylic acid (300 mg, 1.52 mmol) was dissolved in methanol (10 mL), and sodium methoxide (162 mg, 3.04 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the pH of the reaction solution was adjusted to 6 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography using dichloromethane / methanol (15:1) as the developing solvent to obtain 3-oxooctahydroindene-7-carboxylic acid (yellow solid, 150 mg, 53.8%). MS (ESI) + m / z = 184.2[M+H] + .

[0687] Preparation of intermediate H12, 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid

[0688] Methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (2 g, 12.5 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and an aqueous solution of lithium hydroxide (0.79 g, 18.7 mmol) (10 mL) was added. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, the mixture was allowed to return to room temperature. The pH of the reaction solution was adjusted to 2 with 10 M phosphoric acid. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (yellow oil, 1.4 g, 76.7%). MS (ESI) + m / z = 145.1 [M+H] + .

[0689] Preparation of intermediate H13, 1-cyclopropylpiperidine-4-carboxylic acid

[0690] Step 1: Under nitrogen protection, 1-cyclopropylpiperidin-4-one (2 g, 14.4 mmol) was dissolved in a mixed solution of ethylene glycol dimethyl ether and ethanol (v / v = 30 / 1, 20 mL). The solution was cooled to 0 °C, and TOSMIC (3.65 g, 18.7 mmol) and potassium tert-butoxide (3.72 g, 33.1 mmol) were added. The mixture was stirred at 0 °C for 1 h, then heated to 25 °C and stirred for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane / methanol (150 / 1) as the eluent to obtain 1-cyclopropylpiperidin-4-onitrile (yellow oil, 1.1 g, 50.9%). MS (ESI) + m / z = 151.2[M+H] + .

[0691] Step 2: Under nitrogen protection, 1-cyclopropylpiperidin-4-onitrile (1 g, 6.7 mmol) was dissolved in hydrochloric acid (6 M, 10 mL), and the mixture was heated to 100 °C and stirred for 3 h. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain 1-cyclopropylpiperidin-4-carboxylic acid (yellow solid, 1 g, 87.7%). MS (ESI) + m / z = 170.3[M+H] + .

[0692] Preparation of intermediates I1-I7 in the ninth preparation example

[0693] Intermediate I1.(S)-1 2 -(chloromethyl)-1 1 ,2 4 ,7,8-Tetramethyl-1 1 H,2 1 Preparation of H-4-oxo-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazolo[4,3-c]pyridine-3(3,4)-pyridinecyclooctane

[0694] Final product 4 (30 mg, 63.8 mmol) was dissolved in a mixed solution of dichloromethane (10 mL) and thionyl chloride (0.5 mL) and stirred at 25 °C for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give (S)-1. 2 -(chloromethyl)-1 1 ,2 4 ,7,8-Tetramethyl-1 1 H,2 1H-4-O-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazolo[4,3-c]pyridine-3(3,4)-pyridinecyclooctane (yellow solid, 30 mg, crude). MS (ESI) + m / z = 489.2[M+H] + .

[0695] Intermediate I2.(R)-1 1 ,2 4 ,3 1 ,7,8-pentamethyl-1 1 H,2 1 H,3 1 H-4-O-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclooctane-1 2 Preparation of amines

[0696] Intermediate E22 (300 mg, 0.69 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (v / v = 2 / 1, 12 mL), and cyanogen bromide (293 mg, 2.77 mmol) was added. The mixture was stirred at 25 °C for 4 h. After the reaction was complete, the mixture was filtered, and the residue was collected and dried to give (R)-1. 1 ,2 4 ,3 1 ,7,8-pentamethyl-1 1 H,2 1 H,3 1 H-4-O-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclooctane-1 2 -Amine (gray solid, 150 mg, 47.3%). MS (ESI) + m / z = 495.3 [M+H] + .

[0697] Intermediate I3.(S)-1 1 ,2 4 ,3 1 ,8,9-pentamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane-1 2 Preparation of amines

[0698] (S)-1 was prepared using intermediate E20 as a raw material, following the method for synthesizing intermediate I2. 1 ,2 4 ,3 1 ,8,9-pentamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4),2(1,6)-diimidazo[4,5-c]pyridine-3(4,5)-pyrazolcyclononane-1 2 -Amine (yellow solid, 150 mg, 56.8%). MS (ESI) + m / z = 473.3 [M+H] + .

[0699] Intermediate I4.(S)-(1 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane-1 2 Preparation of 1-Based Methanol

[0700] Using intermediate E16 and ethyl 2-chloro-2-oxoethyl acetate as raw materials, (S)-(1)-(2-chloro-2-oxoethyl acetate) was prepared according to the method for synthesizing final product 8. 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane-1 2 1-Based) Methanol (yellow solid, 50 mg, 83.3%). MS (ESI) + m / z = 502.4[M+H] + .

[0701] Intermediate I5.(S)-1 2 -(chloromethyl)-1 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1H,3 1 Preparation of H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane

[0702] (S)-1 was prepared using intermediate I4 as a raw material, following the method for synthesizing intermediate I1. 2 -(chloromethyl)-1 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane (yellow solid, 50 mg, 96.5%). MS (ESI) + m / z = 520.2[M+H] + .

[0703] Intermediate I6.(S)-1 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazole[4,3-c]pyridine-3(4,5)-pyrazolecyclononane-1 2 - Formaldehyde preparation

[0704] (S)-1 was prepared using intermediate I4 as a raw material, following the method in the second step of the synthesis of intermediate D1. 1 ,2 4 ,3 1 ,3 3 ,8,9-Hexamethyl-1 1 H,2 1 H,3 1 H-4-oxa-9-aza-1(6,4),2(1,6)-diimidazo[4,5-c]pyridine-3(4,5-pyrazolonaphthyl-1 2 - Formaldehyde (yellow solid, 40 mg, 40.2%). MS (ESI) + m / z = 500.3[M+H] + .

[0705] Intermediate I7.(S)-1 1 ,7,8-Trimethyl-1 1 H,2 1 H-4-oxa-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazolo[4,3-c]pyridine-3(3,4-)-pyridinecyclooctane-1 2 Preparation of amines

[0706] (S)-1 was prepared using intermediate E14 as a raw material, following the method for synthesizing intermediate I2. 1 ,7,8-Trimethyl-1 1 H,2 1 H-4-oxa-8-aza-1(6,4)-imidazo[4,5-c]pyridine-2(1,6)-pyrazolo[4,3-c]pyridine-3(3,4-)-pyridinecyclooctane-1 2 -Amine (yellow solid, 55 mg, 39.9%). MS (ESI) + m / z = 442.2[M+H] + .

[0707] Preparation of the final product in t...

Claims

1. A heteroaryl macrocyclic compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof. in, In equation I, Ring A is a 5-14-membered heteroaryl, a 3-12-membered heterocyclic, or a 6-12-membered aryl, wherein the 5-14-membered heteroaryl, 3-12-membered heterocyclic, or 6-12-membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1 replace; The E ring is a 5-14-membered heteroaryl, 6-12-membered aryl, or 3-12-membered heterocyclic group, wherein the 5-14-membered heteroaryl, 6-12-membered aryl, or 3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace; The M ring is a 5-14-membered heteroaryl, 6-12-membered aryl, 3-12-membered heterocyclic, 3-12-membered cycloalkyl, or 3-12-membered cycloalkenyl group, wherein the 5-14-membered heteroaryl, 6-12-membered aryl, 3-12-membered heterocyclic, 3-12-membered cycloalkyl, or 3-12-membered cycloalkenyl group is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace; L1 represents chemical bonds, NH, CH2, O, S, C=O, or S(=O)(W 1 The NH and CH2 are optionally separated by one or two identical or different R atoms. 4 replace; L2 is C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl group, containing 1-3 radicals selected from N, O, S, S(=O)(W 1 C atoms 1-10 Heteroalkylene groups, containing 1-3 ions selected from N, O, S, S(=O)(W 1 C atoms 2-10 Heteroeneyl, 3-12 membered heterocyclic group -C 0-6 Alkyl, 3-12 membered cycloalkyl-C 0-6 Alkyl, C 1-6 alkyl-3-12-membered heterocyclic-C 0-6 Alkyl or C 1-6 Alkyl-3-12-membered cycloalkyl-C 0-6 Alkyl, the C 1-10 Alkylene, C 2- 10 imidene group, C 2-10 Alynyl group, containing 1-3 radicals selected from N, O, S, S(=O)(W 1 C atoms 1-10 Heteroalkylene groups, containing 1-3 ions selected from N, O, S, S(=O)(W 1 C atoms 2-10 Heteroeneyl, 3-12 membered heterocyclic group -C 0-6 Alkyl, 3-12 membered cycloalkyl-C 0-6 Alkyl, C 1-6 alkyl-3-12-membered heterocyclic-C 0-6 Alkyl, C 1-6 Alkyl-3-12-membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace; X1, X2, and X3 are each an independent chemical bond, NR 1a -C(R) 2a (R) 3a )-, O, S, C (=O) or S (=O)(W 1 ); R 1 Hydrogen atom, deuterium atom, halogen, CN, NO2, amino, hydroxyl, 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 The amino, hydroxyl, and 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 It can be optionally replaced by one or more R′; R 2 R 3 Each can be independently represented as a hydrogen atom, a deuterium atom, a halogen, CN, NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR 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 C 0-6 Alkyl-S(=O)(W 1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)OR e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)(W 1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′; Or, two Rs 2 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′. Or, X1 and R 2 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′. Or, two Rs 3 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′. Or, X2 and R 3 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl or 6-14-membered aryl groups are optionally substituted by one or more R′. R 4 Each is independently a hydrogen atom, deuterium atom, halogen, or carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl may be optionally substituted by one or more R′; R 5 Each can be independently represented as a hydrogen atom, a deuterium atom, a halogen, CN, NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 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 R e2 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 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 aryl-C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 The alkyl group is optionally substituted with one or more R′; Or, two Rs 5 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl groups are optionally substituted by one or more R′. R 1a R 2a Each is independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 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 R e2 C(=O)OR e1 S(=O)(W) 1 )NR e1 R e2 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 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more R′; R 3a Hydrogen atom, deuterium atom, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 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 R e2 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 oxidized (=O), the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more R′; Or, R 2a and R 3a Together with their respective C atoms, they form 3-12 membered cycloalkyl or 3-12 membered heterocyclic groups, which are optionally substituted by one or more R′; R′ represents a deuterium atom, halogen, CN, NO2, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 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 C 0-6 Alkyl-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 R f2 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 oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″; R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 aryl or C 0-6 alkyl-5-10 heteroaryl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-6-10 aryl, C 0-6 Alkyl-5-10 heteroaryl groups are optionally surrounded by one or more R″; Or, R e1 and R e2 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; Or, R e2 and R e3 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; Or, R f1 and R f2 Together with the linked atoms, it forms a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally substituted by one or more of the following groups: deuterium atom, halogen, CN, NO2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; R″ represents deuterium, halogen, CN, NO2, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 OC(=O)R g1 OC (=O)NR g1 R g2 OS(=O)R g1 OS(=O)(W) 1 )R g1 OS(=O)NR g1 R g2 OS(=O)(W) 1 )NR g1 R g2 SR g1 S(=O)R g1 S(=O)(W) 1 )R g1 S(=O)NR g1 R g2 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 S(=O)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 oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl groups are optionally substituted by one or more of the following groups: deuterium, halogen, CN, hydroxyl, amino, C. 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, OR g1 ; R g1 R g2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl or 3-12 membered heterocyclic, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 The alkenyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group may optionally be substituted by one or more of the following groups: deuterium atom, halogen, CN, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkyl groups, 3-12 membered cycloalkoxy groups; W 1 =None, =O or =NR g1 .

2. The heteroaryl macrocyclic compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate, wherein, The compound has the structural formula shown in Formula II. The definitions of A, E, M, X1, X2, and L2 are as described in claim 1.

3. The heteroaryl macrocyclic compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate, or solvate, wherein, In formula I or II, ring A is a 5-10 membered heteroaryl or a 6-10 membered aryl, wherein the 5-10 membered heteroaryl or 6-10 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1 replace; Optionally, ring A is Optionally, 1, 2, 3, or 4 identical or different R... 1 Replace, among which, Indicates a single bond or a double bond; Z 1 Z 2 Each can be independently N, NH, CH, O, S, C=O or S(=O)(W 1 ); Z 3 Z 4 Z 5 Each can be either N or CH independently; Z 6 Z 7 Z 8 Each can be N or C independently; Further, alternatively, ring A is selected from the following groups: Among them, R 1a′ R 1b′ R 1c′ R 1d′ R 1e′ Each independently as R 1 ; Optionally, R 1 For hydrogen atoms, deuterium atoms, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, hydroxyl, cyano, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, CHO or C(=O)NH2, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, CHO or C(=O)NH2 is optionally substituted with one or more deuterium atoms, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, methoxy, ethoxy, isopropoxy, cyclopropoxy; Further optional, R 1 It can be hydrogen atom, deuterium atom, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trideutermethyl, trifluoroethyl, hydroxyethyl, ethylene, propylene, acetylene, propyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, cyano, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, methoxy, ethoxy, cyclopropoxy, trifluoromethoxy, trifluoroethoxy, oxo, CHO, C(=O)NH2, C(=O)CH3, C(=O)-cyclopropyl or C(=O)N(CH3)2.

4. The heteroaryl macrocyclic compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, or solvate, wherein, In formula I or II, ring E is a 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group, wherein the 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace; Optionally, ring E is The Optionally, 1, 2, 3, or 4 identical or different R... 2 replace; in, Indicates a single bond or a double bond; The B ring is absent or is a 5-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a 6 membered aryl group; Y 1 Y 2 Each can be independently N, NH, CH or CH2; Y 3 For N, NH, C, CH or CH2; when Y 3 When fused with the B ring, Y 3 For N, C or CH; Y 4 Y 5 Each can be independently N, C, or CH; Optionally, the E ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace: Further, alternatively, the E ring is selected from the following groups: in, R 2a′ R 2b′ R 2c′ R 2d′ R 2e′ R 2f′ Each independently as R 2 .

5. The heteroaryl macrocyclic compound according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, or solvate, wherein, In formula I or II, ring M is a 5-6 membered heteroaryl, a 9-10 membered heteroaryl, or a 6 membered aryl, wherein the 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 6 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 3 replace; Optionally, the M ring is benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole, wherein the benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace; Optionally, the M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace: Further optionally, the M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 3 replace: Optionally, R 3 Hydrogen atom, deuterium atom, halogen, CN, hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 , oxo, C(=O)R e1 C(=O)NR e1 R e2 Or S(=O)(W) 1 )R e1 The hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 It can be optionally replaced by one or more R′; Or, two Rs 3 Together with the atoms they are attached to, they form 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups, wherein the 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups are optionally substituted by one or more R′. Or, X2 and R 3 Together with the connected atoms, they form 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups, wherein the 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally substituted by one or more R′. Optionally, R e1 R e2 Each of them independently is methyl, ethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Further optional, R 3 For hydrogen atom, deuterium atom, F, Cl, Br, I, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trideuterated methyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl; Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution.

6. The heteroaryl macrocyclic compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, or solvate thereof, wherein, In formula I or II, L1 is a chemical bond or NH; Optionally, L2 is C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl or 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace; Optionally, R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′; Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′; Optionally, L2 is ethylidene, propyleneidene, butylidene, pentylene, hexylidene, oxapropyleneide, oxabutylidene, azidopropyleneide, azidobutylidene, propenylidene, or butenylidene, wherein the ethylidene, propyleneidene, butylidene, pentylene, hexylidene, oxapropyleneide, oxabutylidene, azidopropyleneide, azidobutylidene, propenylidene, or butenylidene is optionally surrounded by one or more identical or different R... 5 replace; Optionally, R 5 The hydroxyl group, deuterium group, F, Cl, Br, CN, hydroxyl group, hydroxyethyl group, amino group, methylamino group, dimethylamino group, cyclopropylamino group, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziroxybutyl group, aziroxypentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, cyclopropoxy group, or oxo group may be optionally substituted with one or more of the same or different F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclopentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, or cyclopropoxy group; Or, two Rs 5 Together with their respective connected atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperazinyl, and homomorpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperazinyl, and homomorpholinyl groups are optionally substituted by one or more identical or different F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, and methoxy groups; Further, optionally, L2 is selected from the following groups:

7. The heteroaryl macrocyclic compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, or solvate thereof, wherein, In equation I or II, X1 is NR 1a -C(R) 2a (R) 3a - or O; Optionally, X2 is NR 1a -C(R) 2a (R) 3a - or O; Optionally, X3 is a chemical bond, NR 1a -C(R) 2a (R) 3a - or O; Optionally, R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl groups may optionally be substituted with one or more R′; Optionally, R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1- 6-alkylamino, di(C 1-6 alkyl)amino or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino groups and 3-10-membered heterocyclic groups are optionally substituted with one or more R′ groups; Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′; Optionally, R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′; Optionally, R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1- 6-alkylamino, di(C 1-6 alkyl)amino or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 The alkyl)amino group and the 3-7 membered heterocyclic group are optionally substituted with one or more R′ groups; Further optional, R 1a R 2a Each can be independently a hydrogen atom, deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl; Further optional, R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy; Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′ groups. Optionally, R′ can be a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, or oxo.

8. The heteroaryl macrocyclic compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, or solvate thereof, wherein, R 2 Hydrogen atom, deuterium atom, halogen, CN, nitro, C 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 S(=O)(=NR) g1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)(W 1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′; Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′. Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′; Optionally, R′ can be a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0- 6-alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″; Optionally, R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic and 5-10 membered heteroaryl are optionally substituted by one or more R″; Optionally, R″ is a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, cyano, and oxo substitutions; Optionally, R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, C(=O)C 1-3 Alkyl substitution; Optionally, R 2 Each is independently a hydrogen atom, deuterium atom, halogen, CN, nitro, C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 S(=O)(=NR) e2 )R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0- 3alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′; Optionally, R′ can be a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0- 3alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 P(=O)R f1 R f2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-3 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″; Optionally, R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic or 5-6 membered heteroaryl, said C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic and 5-6 membered heteroaryl groups are optionally substituted by one or more R″; Optionally, R″ is a deuterium atom, a halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 S(=O)(W) 1 )R g1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic groups optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1- 6-alkoxy, cyano, and oxo-substituted; Optionally, R 2 Each of these groups can be independently a hydrogen atom, deuterium atom, halogen, nitro group, hydroxyl group, CN group, methyl group, ethyl group, isopropyl group, trideuterated methyl group, difluoromethyl group, trifluoromethyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, difluoroethoxy group, trifluoroethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, mercapto group, methyl mercapto group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or selected from the following groups: Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups; Or, X1 and R 2 Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups; Optionally, R g1 R g2 Each of the following is independently a hydrogen atom, methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, or oxo.

9. The heteroaryl macrocyclic compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated derivative, N-oxide, prodrug molecule, hydrate, or solvate thereof, wherein, In formula I or II, Ring A is a 5-10 membered heteroaryl or a 6-10 membered aryl, wherein the 5-10 membered heteroaryl or 6-10 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 1 replace; The E ring is a 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group, wherein the 6-10 aryl, 5-10 heteroaryl, or 5-10 heterocyclic group is optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace; The M ring is a 5-6 membered heteroaryl, a 9-10 membered heteroaryl, or a 6 membered aryl, wherein the 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 6 membered aryl is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace; L1 is a chemical bond or NR 4 ; L2 is C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl or 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace; X1 is NR 1a -C(R) 2a (R) 3a - or O; X2 is NR 1a -C(R) 2a (R) 3a - or O; X3 is a chemical bond, NR 1a -C(R) 2a (R) 3a - or O; R 1 Hydrogen atom, deuterium atom, halogen, CN, NO2, amino, hydroxyl, 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 The amino, hydroxyl, and 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 heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, C(=O)R e1 Or C(=O)NR e1 R e2 It can be optionally replaced by one or more R′; R 2 R 3 Each can be independently represented as a hydrogen atom, deuterium atom, halogen, CN, nitro group, or C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0-6 Alkyl-S(=O)2R e1 S(=O)(=NR) g1 )R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 Or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-6 Alkyl-3-12-membered cycloalkyl, C 0-6 Alkyl-3-12-membered heterocyclic group, C 0-6 Alkyl-5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclic -C 1-6 Alkyl, 5-10 heteroaryl-C 1-6 Alkyl, C 0-6 Alkyl-OR e1 C 0-6 Alkyl-SR e1 C 0-6 Alkyl-S(=O)R e1 C 0- 6-alkyl-S(=O)2R e1 C 0-6 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-6 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′; Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′. Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′; Or, two Rs 3 Together with the atoms they are attached to, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, and 6-14-membered aryl groups are optionally substituted by one or more R′. Or, X2 and R 3 Together with the connected atoms, they form 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, or 6-14-membered aryl groups, wherein the 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclic, 5-14-membered heteroaryl, and 6-14-membered aryl groups are optionally substituted by one or more R′. R 4 It is a hydrogen atom; R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1- 6-alkylamino, di(C 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′; Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′; R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl, wherein the C 1- 6-alkyl, halogenated C 1-6 Alkyl or 3-12 membered cycloalkyl groups may optionally be substituted with one or more R′; R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, 3-10 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino groups and 3-10-membered heterocyclic groups are optionally substituted with one or more R′ groups; Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′; R′ represents a deuterium atom, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-6 Alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-6 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″; R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic and 5-10 membered heteroaryl are optionally substituted by one or more R″; R″ represents deuterium, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, cyano, and oxo substitutions; R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, C(=O)C 1-3 Alkyl substitution; W 1 =None, =O or =NR g1 ; Optionally, ring A is Optionally, 1, 2, 3, or 4 identical or different R... 1 Replace, among which, Indicates a single bond or a double bond; Z 1 Z 2 Each can be independently N, NH, CH, O, S, C=O or S(=O)(W 1 ); Z 3 Z 4 Z 5 Each can be either N or CH independently; Z 6 Z 7 Z 8 Each can be N or C independently; E ring is The Optionally, 1, 2, 3, or 4 identical or different R... 2 Replace; among them, Indicates a single bond or a double bond; The B ring is absent or is a 5-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a 6 membered aryl group; Y 1 Y 2 Each can be independently N, NH, CH or CH2; Y 3 For N, NH, C, CH or CH2; when Y 3 When fused with the B ring, Y 3 For N, C or CH; Y 4 Y 5 Each can be independently N, C, or CH; The M ring is benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole, wherein the benzene, pyridine, pyrimidine, pyridazine, pyridinone, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyrrole, or triazole is optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace; L1 represents a chemical bond or NH; L2 is C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl, the C 1-6 Alkylene, C 1-6 alkenyl groups, containing 1-3 radicals selected from N, O, S, C (=O), S (=O) (W 1 C atoms 1-6 Heteroalkylene, 3-7 membered heterocyclic -C 0-6 Alkyl, 3-7 membered cycloalkyl-C 0-6 Alkyl groups are optionally surrounded by one or more identical or different R groups. 5 replace; X1 is NR 1a -C(R) 2a (R) 3a - or O; X2 is NR 1a -C(R) 2a (R) 3a - or O; X3 is a chemical bond; R 1 Each is independently a hydrogen atom, deuterium atom, halogen, or carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered cycloalkyl, hydroxyl, cyano, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, CHO, C(=O)NH2, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-12 membered cycloalkyl, hydroxyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, CHO, C(=O)NH2 are optionally substituted by one or more F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxy, cyano, methoxy, ethoxy, isopropoxy, cyclopropoxy; R 2 Each is independently a hydrogen atom, deuterium atom, halogen, CN, nitro, C. 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0- 3-alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 S(=O)(=NR) e2 )R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 NR e1 R e2 NR e1 C(=O)R e2 C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 NR e1 C(=O)NR e2 R e3 NR e1 S(=O)(W 1 )NR e2 R e3 C(=O)R e1 C(=O)NR e1 R e2 N = S(=O)R e2 R e3 、or C(=O)OR e1 The C mentioned 1-6 Alkyl, C 2-6 alkynyl group, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group, C 0-3 Alkyl-8-10 membered heterocyclic groups, C 0-3 Alkyl-5-6-membered heteroaryl, 3-6-membered cycloalkyl-C 1-3 Alkyl, 3-7 membered heterocyclic -C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-6 Alkyl, C 0-3 Alkyl-OR e1 C 0-3 Alkyl-SR e1 C 0-3 Alkyl-S(=O)R e1 C 0-3 Alkyl-S(=O)2R e1 C 0-3 Alkyl-S(=O)(W 1 )NR e1 R e2 Or C 0-3 Alkyl-NR e1 S(=O)(W 1 )R e2 It can be optionally replaced by one or more R′; R 3 Hydrogen atom, deuterium atom, halogen, CN, hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 , oxo, C(=O)R e1 C(=O)NR e1 R e2 Or S(=O)(W) 1 )R e1 The hydroxyl group, C 1-6 Alkyl, NR e1 R e2 C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-OR e1 It can be optionally replaced by one or more R′; Or, two Rs 2 Together with the atoms they are attached to, they form 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl, wherein the 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocyclic, 5-6 membered heteroaryl or 6 membered aryl are optionally substituted by one or more R′. Or, X1 and R 2 The connected atoms together form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group, wherein the 3-6 membered cycloalkyl, a 4-7 membered heterocyclic group, a phenyl or a 5-6 membered heteroaryl group is optionally substituted by one or more R′; Or, two Rs 3 Together with the atoms they are attached to, they form 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups, wherein the 3-7-membered cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl or 6-membered aryl groups are optionally substituted by one or more R′. Or, X2 and R 3 Together with the connected atoms, they form 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups, wherein the 3-6-membered cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups are optionally substituted by one or more R′. R 5 It consists of hydrogen atoms, deuterium atoms, halogens, CN, amino groups, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1- 6-alkylamino, di(C 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 Alkyl-3-7-membered heterocyclic group or oxo, wherein the amino group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkoxy, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 0-3 Alkyl-3-6 membered cycloalkyl, C 0-3 The alkyl-3-7-membered heterocyclic group is optionally substituted with one or more R′; Or, two Rs 5 Together with the atoms they are attached to, they form 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups, wherein the 3-7 membered cycloalkyl, 3-7 membered heterocyclic or 3-6 membered cycloalkenyl groups are optionally substituted by one or more R′; R 1a R 2a Each can be independently composed of a hydrogen atom, a deuterium atom, a halogen, a cyano group, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1- 6-alkyl, halogenated C 1-6 Alkyl or 3-6 membered cycloalkyl groups may optionally be substituted with one or more R′; R 3a Hydrogen atom, deuterium atom, halogen, CN, C 1-6 Alkyl, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C) 1-6 alkyl)amino, 3-7 membered heterocyclic group, wherein C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C) 1-6 The alkyl)amino group and the 3-7 membered heterocyclic group are optionally substituted with one or more R′ groups; Or, R 2a and R 3a Together with the connected C atom, a 3-6 membered cycloalkyl group is formed, wherein the 3-6 membered cycloalkyl group is optionally substituted by one or more R′; R′ represents a deuterium atom, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, OR f1 C 0-3 Alkyl-S(=O)(W 1 )R f1 S(=O)(W) 1 )NR f1 R f2 NR f1 R f2 NR f1 S(=O)(W 1 )R f2 C(=O)OR f1 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, C 0-3 Alkyl-S(=O)(W 1 )R f1 Optionally replaced by one or more R″; R e1 R e2 R e3 R f1 R f2 Each is independently a hydrogen atom, a deuterium atom, and a carbon atom. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic or 5-6 membered heteroaryl, said C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic and 5-6 membered heteroaryl groups are optionally substituted by one or more R″; R″ represents deuterium, halogen, CN, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, OR g1 NR g1 R g2 S(=O)(W) 1 )NR g1 R g2 Or oxidized (=O), the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic groups optionally surrounded by one or more halogens, hydroxyl groups, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, (C 1-6 alkyl)2amino, C 1-6 Alkyl, cyano, and oxo substitutions; R g1 R g2 Each is independently a hydrogen atom, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl groups are optionally surrounded by one or more halogens, hydroxyl groups, C-type alkyl groups. 1-3 Alkyl, Halogenated C 1-3 Alkyl, amino, C 1-3 Alkylamino, (C 1-3 alkyl)2amino, C 1-6 Alkoxy, cyano, oxo, C(=O)C 1-3 Alkyl substitution; W 1 =None, =O or =NR g1 ; Further, alternatively, ring A is selected from the following groups: The E ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R groups. 2 replace: The M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace: L1 represents a chemical bond or NH; L2 is ethylene, propyleneene, butylene, pentylene, hexylene, oxapropyleneene, oxabutylene, aziridine, aziridine, propenylene, or butenylene, wherein the ethylene, propyleneene, butylene, pentylene, hexylene, oxapropyleneene, oxabutylene, aziridine, aziridine, propenylene, or butenylene is optionally surrounded by one or more identical or different R groups. 5 replace; X1 is NR 1a -C(R) 2a (R) 3a - or O; X2 is NR 1a -C(R) 2a (R) 3a - or O; X3 is a chemical bond; R 2 Each of these groups can be independently a hydrogen atom, deuterium atom, halogen, nitro group, hydroxyl group, CN group, methyl group, ethyl group, isopropyl group, trideuterated methyl group, difluoromethyl group, trifluoromethyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, difluoroethoxy group, trifluoroethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, mercapto group, methyl mercapto group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or selected from the following groups: Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups; Or, X1 and R 2 Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups; R 3 For hydrogen atom, deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl; Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution; R 5 The hydroxyl group, deuterium group, F, Cl, Br, CN, hydroxyl group, hydroxyethyl group, amino group, methylamino group, dimethylamino group, cyclopropylamino group, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziroxybutyl group, aziroxypentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, cyclopropoxy group, or oxo group may be optionally substituted with one or more of the same or different F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclopentyl group, oxacyclobutyl group, oxacyclopentyl group, methoxy group, ethoxy group, or cyclopropoxy group; Or, two Rs 5 Together with their respective connected atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperazinyl, and homomorpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, oxacyclobutyl, oxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperazinyl, and homomorpholinyl groups are optionally substituted by one or more identical or different F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, hydroxyl, cyano, and methoxy groups; R 1a R 2a Each can be independently a hydrogen atom, deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl; R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy; Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′ groups. R′ can be a deuterium atom, halogen, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, or oxo. R g1 The methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, and oxo groups. W 1 =None, =O or =NR g1 ; R 1a′ R 1b′ R 1c′ R 1d′ R 1e′ Each independently as R 1 ;R 1 The following are the possible values: hydrogen atom, deuterium atom, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, ethylene, propylene, acetylene, propyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, cyano, amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, methoxy, ethoxy, cyclopropoxy, oxo, CHO or C(=O)NH2; Further, alternatively, in formula I or II, Ring A is selected from the following groups: The E ring is selected from the following groups: The M ring is selected from the following groups, which are optionally surrounded by 1, 2, 3, or 4 identical or different R rings. 3 replace: L1 represents a chemical bond or NH; L2 is selected from the following groups: X1 is NR 1a -C(R) 2a (R) 3a - or O; X2 is NR 1a -C(R) 2a (R) 3a - or O; X3 is a chemical bond; R 2a′ R 2b′ R 2c′ R 2d′ R 2e′ R 2f′ Each independently as R 2 ; R 2 It can be a hydrogen atom, deuterium atom, halogen, nitro, hydroxyl, CN, methyl, ethyl, isopropyl, trideuterated methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, mercapto, methylmercapto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or selected from the following groups: Or, two Rs 2 Together with the atoms to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3-dioxolane, 1,4-dioxaspiro[4.4]nonane, oxazolyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazine, piperidinyl, hexahydropyrimidinyl, morpholinyl, or tetrahydroimidazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 1,3- Dioxapentane, 1,4-dioxaspiro[4.4]nonane, oxazolidinyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl or tetrahydroimidazolyl are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups or oxo groups; Or, X1 and R 2 Together with the linked atoms, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, or phenyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, piperazinyl, piperidinyl, hexahydropyrimidinyl, morpholinyl, tetrahydroimidazolyl, pyrimidinyl, pyridinyl, and phenyl groups are optionally substituted with one or more deuterium atoms, halogens, amino groups, hydroxyl groups, CN groups, methyl groups, ethyl groups, difluoromethyl groups, difluoroethyl groups, trifluoromethyl groups, trifluoroethyl groups, isopropyl groups, methoxy groups, ethoxy groups, or oxo groups. R 3 For hydrogen atom, deuterium atom, F, Cl, Br, CN, hydroxyl, hydroxyethyl, amino, methylamino, dimethylamino, cyclopropylamino, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, oxo, C(=O)H, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2 or S(=O)(W 1 )-Cyclopropyl; Or, X2 and R 3 Together with the linked atoms, they form pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles, wherein the pyrroles, imidazoles, thiazoles, oxazoles, isothiazoles, isoxazoles, or pyrazoles are optionally bonded by one or more of the same or different F, Cl, Br, CN, methyl, ethyl, cyclopropyl, dimethylamino, C(=O)CH3, C(=O)-cyclopropyl, C(=O)N(CH3)2, or S(=O)(W 1 )-Cyclopropyl substitution; R 1a R 2a Each can be independently a hydrogen atom, deuterium atom, F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trideuterated methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or hydroxyethyl; R 3a It can be hydrogen atom, deuterium atom, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, amino, methylamino, dimethylamino, methoxy, ethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, or trifluoroethoxy; Or, R 2a and R 3a Together with the linked C atom, it forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is optionally substituted by one or more R′ groups; W 1 =None, =O or =NR g1 ; R g1 R g2 Each of the following is independently a hydrogen atom, methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, n-propyl, difluoromethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, or cyclobutyl groups are optionally substituted by one or more F, Cl, Br, hydroxyl, methyl, ethyl, amino, methylamino, dimethylamino, methoxy, cyano, or oxo groups. Alternatively, the compound represented by formula I or II may be selected from the following compounds:

10. A pharmaceutical composition comprising any one of the heteroaryl macrocyclic compounds as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient. Optionally, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, or spray.

11. The use of any heteroaryl macrocyclic compound or pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated product, N-oxide, prodrug molecule, hydrate or solvate of any one of claims 1 to 9 and / or the pharmaceutical composition of claim 10 in the preparation of a medicament for treating EGFR-mediated diseases; Optionally, the disease is a neoplastic disease; Further, optionally, the neoplastic disease includes: Head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, stomach 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.

12. A method for treating EGFR-mediated diseases, the method comprising administering to a patient in need a heteroaryl macrocyclic compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotope label, deuterated compound, N-oxide, prodrug molecule, hydrate or solvate thereof and / or a pharmaceutical composition of claim 10; Optionally, the disease is a neoplastic disease; Further, optionally, the neoplastic disease includes: Head and neck cancer, nasopharyngeal carcinoma, melanoma, bladder cancer, esophageal cancer, kidney cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, prostate cancer, leukemia, lymphoma, stomach cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, bile duct cancer, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis or pulmonary fibrosis.

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