Pyrimidine or pyridine derivatives, their preparation methods, and their pharmaceutical applications

Abstract

A pyrimidine or pyridine derivative having the structure of formula (I), a method for its preparation, a pharmaceutical composition containing the same, and its use as an EGFR inhibitor and its use in the preparation of medicaments for the treatment and / or prevention of cancer, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertions, deletions or other mutations, particularly in the preparation of medicaments for the treatment and / or prevention of hyperproliferative diseases and diseases inducing cell death disorders.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to pyrimidine or pyridine derivatives, their preparation methods, and their pharmaceutical applications. Background Technology

[0002] Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all deaths. Multi-target therapies targeting epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangements, the B-raf proto-oncogene, and serine / threonine kinase (BRAF) have been successfully developed and clinically validated. EGFR inhibitors significantly improve progression-free survival in adenocarcinomas of NSCLC, and acquired resistance mutations can be targeted by third-generation EGFR inhibitors.

[0003] While classic EGFR activating mutations (exons 19 and 21) and drug-resistance mutations (T790M) can be inhibited by existing drugs, exon 20 insertion mutations also lead to structural activation of EGFR signaling and are insensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous, including insertions or duplications of 1–7 amino acids between amino acids 762–774 of the EGFR protein. In NSCLC, EGFR exon 20 mutations account for 4–10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogene driver mutations and are enriched in adenocarcinomas in women, nonsmokers, Asian populations, and non-small cell lung cancer patients. Besides NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, nasal squamous cell carcinoma (SNSCC). Furthermore, structurally similar exon 20 insertion mutations have been found in HER2, another member of the EGFR family.

[0004] Multiple retrospective analyses have shown that currently available first-, second-, and third-generation EGFR inhibitors have limited efficacy against exon 20 insertion mutations, except for the A763-Y764insFQEA mutation. The irreversible inhibitor poziotinib and the EGFR / MET bispecific antibody amivantamab are currently in clinical trials. Several small-molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in patients with EGFR exon 20 non-small cell lung cancer. However, due to their limited selectivity for EGFR wild-type, adverse reactions are unavoidable in clinical use and may lead to dose-limiting toxicities. Furthermore, clinical studies have shown that existing compounds may have insufficient exposure. Therefore, there is an urgent need for small-molecule inhibitors with higher exposure and / or high selectivity against EGFR exon 20 insertion mutations in these patients. Summary of the Invention

[0005] The purpose of this invention is to provide a pyrimidine or pyridine derivative, its preparation method, and its pharmaceutical application. The series of compounds of this invention have a strong inhibitory effect on the cellular activity of EGFR exon 20 insertion, deletion, or other mutations, and have high selectivity for EGFR wild type. They can be widely used in the preparation of drugs for the treatment and / or prevention of at least some cancers, tumors, or metastatic diseases related to EGFR exon 20 insertion, deletion, or other mutations, especially drugs for the treatment of hyperproliferative diseases and diseases that induce cell death disorders, thus promising the development of a new generation of EGFR inhibitors.

[0006] The first aspect of the present invention provides a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Where X is CH or N; Y1 and Y2 are each independently CH or N; Z is CR 11 Or N;

[0009] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 Or, R1 and its adjacent R 10 Together with the part directly connected to it, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced;

[0010] R 2a and R 2b Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or, R 2a and R 2b Together with the carbon atom directly attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced;

[0011] R 3a and R 3b Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0012] R4 is selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The substituents are replaced;

[0013] R5 is selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0014] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 ;

[0015] R7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15)-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 ;

[0016] R8 and R9 are each independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl groups and 3-6-membered heterocyclic groups, or R8 and R9 together with the nitrogen atom directly attached to them to form 3-12-membered heterocyclic groups, wherein the above groups are optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The substituents are replaced;

[0017] Alternatively, one of R6, R7, or R9 and R5 together with the portion directly attached to it form a 4-6 membered heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0018] Alternatively, R7 and R8 together with their directly attached portions form a 4-6 membered heterocyclic group, which may optionally be further substituted with one or more elements selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0019] or, It has the following structure: R8 is as defined above;

[0020] Each R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 Or, when m=2, the two Rs 10 Together with the part directly connected to it, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups;

[0021] R 11Selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 ;

[0022] Each R 12 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl and -C 0-8 Alkyl-NR 15 R 16 The above-mentioned groups may optionally be further substituted with one or more radicals selected from deuterium, halogen, hydroxyl, oxo, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The substituents are replaced;

[0023] Each R 13 Each is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The substituents are replaced;

[0024] Each R 14 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -C 0-8 Alkyl-NR 15 R 16 The substituents are replaced;

[0025] Each R 15 and R 16 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-10 Alkoxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 Alkyl group, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 Substituents of the alkyl acyl group,

[0026] Or, R 15 and R 16 Together with the nitrogen atom directly attached thereto, a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, which may optionally be further bonded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is replaced by a substituent;

[0027] m is 0, 1, or 2;

[0028] n is 0, 1, or 2; and

[0029] Each r is independently 0, 1, or 2.

[0030] As a preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salt, Z is CR 11 Or N;

[0031] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 Or, R1 and its adjacent R 10 Together with the part directly connected to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced;

[0032] R 2a and R 2b Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 quinone heteroaryl, or, R 2a and R 2b Together with the carbon atom directly attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced;

[0033] R 3a and R 3b Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl and 5-8 quinone heteroaryl groups;

[0034] R4 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C0-4 Alkyl-NR 15 R 16 The substituents are replaced;

[0035] R5 is selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0036] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 ;

[0037] R7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 ;

[0038] R8 and R9 are each independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic groups, or R8 and R9 together with the nitrogen atom directly attached to them to form 3-6 membered heterocyclic groups, wherein the above groups are optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16 The substituents are replaced;

[0039] Alternatively, one of R6, R7, or R9 and R5 together with the portion directly attached to it form a 4-6 membered heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0040] Alternatively, R7 and R8 together with their directly attached portions form a 4-6 membered heterocyclic group, which may optionally be further substituted with one or more elements selected from deuterium, halogen, cyano, nitro, azido, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8Aryl, 5-8 heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0041] or, It has the following structure: R8 is as defined above;

[0042] Each R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R 16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 Or, when m=2, the two Rs 10 Together with the part directly connected to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0043] R 11 Selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 12 -C 0-4 Alkyl-OR 13 -C 0-4 Alkyl-C(O)OR 13 -C 0-4 Alkyl-C(O)R 14 -C 0-4 Alkyl-OC(O)R 14 -C 0-4 Alkyl-NR 15 R 16 -C 0-4 Alkyl-C (=NR) 15 )R 14 -C 0-4 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-4 Alkyl-C(O)NR 15 R16 and -C 0-4 Alkyl-N(R) 15 )-C(O)R 14 ;and

[0044] Among them, R 12 R 13 R 14 R 15 R 16 m, n and r are as described in compound (I).

[0045] As a preferred embodiment, each R in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, 12 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl and -C 0-4 Alkyl-NR 15 R 16 The above-mentioned groups may optionally be further substituted with one or more radicals selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16 The substituents are replaced;

[0046] Each R 13 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16The substituents are replaced;

[0047] Each R 14 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16 The substituents are replaced;

[0048] Each R 15 and R 16 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 Alkyl group, wherein the above groups are optionally further divided by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 Substituents of the alkyl acyl group,

[0049] Or, R 15 and R 16 Together with the nitrogen atom directly attached thereto, a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, which may optionally be further bonded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl group is replaced by a substituent.

[0050] As a preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is a compound of formula (II) as follows:

[0051]

[0052] Where Y1 is CH or N; Z is CH or N;

[0053] R1 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16-C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 Or, R1 and R 10 Together with the part directly connected to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 The substituents are replaced;

[0054] R 2a and R 2b Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, or, R 2a and R 2b Together with the carbon atom directly attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 The substituents are replaced;

[0055] R 3a and R 3b Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0056] R4 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl groups and 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 15 R 16 The substituents are replaced;

[0057] R5 is selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl;

[0058] R6 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 ;

[0059] R7 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 ;

[0060] R8 and R9 are each independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, or R8 and R9 together with the nitrogen atom directly attached to them to form a 3-6 membered heterocyclic group, wherein the above groups are optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy groups, 5-8 heteroaryl groups, 5-8 heteroaryloxy groups and -C 0-4 Alkyl-NR 15 R 16 The substituents are replaced;

[0061] Alternatively, one of R6, R7, or R9 and R5 together with their directly attached portion form a 4-6 membered heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0062] Alternatively, R7 and R8 together with their directly attached portions form a 4-6 membered heterocyclic group, which may optionally be further substituted with one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0063] or, It has the following structure: R8 is as defined above;

[0064] R 10 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14-N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R 16 and -N(R) 15 )-C(O)R 14 ;

[0065] Among them, R 12 R 13 R 14 R 15 R 16 n and r are as described in compound (I).

[0066] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -SF5, -OR 13 -OC(O)R 14 and -NR 15 R 16 Or, R1 and R 10 Together with the part directly connected to it, they form C 4-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, -SF5, -S(O) r R 12 -OR 13 -C(O)OR 13 -C(O)R 14 -OC(O)R 14 -NR 15 R 16 -C(=NR) 15 )R 14 -N(R) 15 )-C(=NR 16 )R 14 -C(O)NR 15 R16 and -N(R) 15 )-C(O)R 14 The substituents are replaced;

[0067] R 2a and R 2b Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl and C 3-6 cycloalkyl, or R 2a and R 2b Together with the carbon atom directly attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 Substituents of cycloalkyl groups;

[0068] R 3a and R 3b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl and C 3-6 cycloalkyl;

[0069] R4 is selected from hydrogen, deuterium, and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the above groups are optionally further divided by one or more radicals selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 15 R 16 The substituents are replaced;

[0070] R5 is selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl;

[0071] R6 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl;

[0072] R7 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl;

[0073] R8 and R9 are each independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, or R8 and R9 together with the nitrogen atom directly attached to them, form a 3-6 membered heterocyclic group, which may optionally be further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and -NR 15 R 16 The substituents are replaced;

[0074] Alternatively, one of R6, R7, or R9 and R5 together with their directly attached portion form a 4-6 membered heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne and C 3-6 Substituents of cycloalkyl groups,

[0075] Alternatively, R7 and R8 together with their directly attached portions form a 4-6 membered heterocyclic group, which may optionally be further substituted with one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne and C 3-6 Substituents of cycloalkyl groups,

[0076] or, It has the following structure: R8 is as defined above;

[0077] R 10 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne and C 3-6 cycloalkyl;

[0078] Among them, R 12 R 13 R 14 R 15 R 16 n and r are as described in compound (II).

[0079] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, pyrazole, imidazole, oxazole, triazole, methoxy, amino, dimethylamino, and methylamino; or, R1 and R 10 Together with the portion directly attached thereto, a cyclopentyl group is formed, which may be further replaced by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteryl, dideuterylmethyl, cyclopropyl, and cyclobutyl.

[0080] R 10 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl.

[0081] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, R4 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, and the above groups are optionally further selected by one or more of deuterium, fluorine, C 1-4 Alkyl and C 3-6 Substituents of cycloalkyl groups.

[0082] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salt, R 2a and R 2b Each is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, or, R 2a and R 2b Together with the carbon atom directly attached thereto, it forms a cyclopropyl, cyclobutyl, or cyclopentyl group, which may be further replaced by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteryl, dideuteryl, cyclopropyl, and cyclobutyl.

[0083] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salt, R 3a and R 3b Each is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl.

[0084] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R5 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, cyclopropyl and cyclobutyl;

[0085] R6 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, cyclopropyl, and cyclobutyl;

[0086] R7 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, cyclopropyl, and cyclobutyl;

[0087] R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, and cyclobutyl, or R8 and R9 together with the nitrogen atom directly attached to them form a 4-6 membered heterocyclic group.

[0088] Alternatively, one of R6, R7, or R9 and R5 together with their directly attached portion form a 4-6 membered heterocyclic heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further composed of one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne and C 3-6 Substituents of cycloalkyl groups,

[0089] Alternatively, R7 and R8 together with their directly attached portions form a 4-6 membered heterocyclic group, which may optionally be further substituted with one or more elements selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne and C 3-6 Substituents of cycloalkyl groups,

[0090] or, It has the following structure: R8 is defined as previously.

[0091] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts are present. It has the following structure:

[0092]

[0093] Each R5 is independently selected from hydrogen, deuterium, methyl, ethyl, trideuterium, and dideuterium;

[0094] Each R6 is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, cyclopropyl, and cyclobutyl;

[0095] R7 is selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl,

[0096] Each R8 and R9 is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, and cyclobutyl, or R8 and R9 together with the nitrogen atom directly attached to them form a 4-6 membered heterocyclic group.

[0097] R a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 cycloalkyl;

[0098] R b Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0099] As the most preferred embodiment, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0111]

[0112] Among them, X, Y1, Y2, Z, R1, R 2a R 2b R 3a R 3b , R4, R5, R6, R7, R8, R9, R 10 m and n are as described in compound (I).

[0113] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0114] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of at least part of cancer, tumor or metastatic disease associated with EGFR exon 20 insertion, deletion or other mutations.

[0115] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

[0116] The present invention also relates to the use of the aforementioned compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for the prevention and / or treatment of at least part of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma.

[0117] The present invention also relates to compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, and their medicaments.

[0118] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof for the treatment and / or prevention of cancer, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertions, deletions or other mutations.

[0119] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

[0120] The present invention also relates to the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof for the treatment and / or prevention of at least some of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma.

[0121] The present invention also relates to a method for treating and / or preventing cancer, tumor, or metastatic disease that is at least partially associated with EGFR exon 20 insertions, deletions, or other mutations, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0122] The present invention also relates to a method for preventing and / or treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induced cell death disorders, comprising administering to a desired patient a therapeutically effective amount of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0123] The present invention also relates to a method for treating and / or preventing at least some of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma, comprising administering to a desired patient a therapeutically effective amount of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0124] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a pyrimidine or pyridine derivative having the structure of formula (I). This series of compounds can be widely used in the preparation of drugs for the treatment and / or prevention of at least some cancers, tumors, or metastatic diseases associated with EGFR exon 20 insertions, deletions, or other mutations, particularly for the treatment of hyperproliferative diseases and diseases inducing cell death disorders, and holds promise for development into a new generation of EGFR inhibitors. Based on this, the present invention was completed.

[0125] Detailed explanation: Unless otherwise stated or specifically stated, the terms used in the specification and claims shall have the following meanings.

[0126] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyl groups with 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and branched alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and 2-methylpentyl. 3-Methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers, etc. "C 1-10 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 10 carbon atoms and branched alkyl groups. 1-4 "Alkyl" refers to straight-chain alkyl groups comprising 1 to 4 carbon atoms and branched alkyl groups. 0-8 "Alkyl" refers to straight-chain alkyl groups comprising 0 to 8 carbon atoms and branched alkyl groups. 0-4 "Alkyl" refers to straight-chain alkyl groups containing 0 to 4 carbon atoms and branched alkyl groups.

[0127] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cyano, nitro, azido, halogen, cyano ... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0128] "Cycloalkyl" or "carbocyclic" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Cycloalkyl groups are classified as monocyclic or polycyclic, and preferably include 3 to 12, 3 to 8, or 3 to 6 carbon atoms. For example, "C..." 3-12 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 12 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0129] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0130] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the rings. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to:

[0131]

[0132] "Fused cyclic alkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring shares an adjacent pair of carbon atoms with the other rings in the system. One or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. Based on the number of constituent rings, fused cyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cyclic alkyl groups include, but are not limited to:

[0133]

[0134] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0135]

[0136] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0137] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cyano, nitro, azido, and C64. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0138] "Heterocyclic group" or "heterocycle" refers to a substituent for a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. In a heterocyclic group, one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it includes heterocyclic groups with 3 to 12, 3 to 8, 3 to 6, or 5 to 6 ring atoms. For example, "3-6 membered heterocyclic group" refers to a cyclic group containing 3 to 6 ring atoms, "3-12 membered heterocyclic group" refers to a cyclic group containing 3 to 12 ring atoms, "5 membered heterocyclic group" refers to a cyclic group containing 5 ring atoms, "5-8 membered heterocyclic group" refers to a cyclic group containing 5 to 8 ring atoms, and "5-10 membered heterocyclic group" refers to a cyclic group containing 5 to 10 ring atoms.

[0139] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.

[0140] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (Where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiroatoms between rings. Spiroheterocyclic groups include, but are not limited to:

[0141]

[0142] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more (preferably 1, 2, 3, or 4) rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r (where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include, but are not limited to:

[0143]

[0144] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O). r Bridged heterocyclic groups consist of heteroatoms (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0145]

[0146] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0147]

[0148] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0149] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, preferably an all-carbon aryl group containing 6-10, 6-8, or 6 carbons, for example, "C 6-10 "Aryl" refers to a fully carbon-based aryl group containing 6-10 carbons. 6-8 "Aryl" refers to a full-carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0150]

[0151] The "aryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0152] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, or 2), preferably containing 5-10, 5-8, or 5-6 ring atoms. For example, "5-8-membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10-membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0153]

[0154] The "heteroaryl" group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0155] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight-chain or branched alkenyl group containing 2-10 or 2-4 carbons, for example, "C 2-10 "Alkenyl" refers to a straight-chain or branched alkenyl group containing 2-10 carbons. 2-4 "Alkenyl" refers to straight-chain or branched alkenyl groups containing 2-4 carbons. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0156] The "alkenyl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 Substituted by a substituent.

[0157] "Alkyne group" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkyne group" refers to a straight-chain or branched alkynyl group containing 2-10 carbons. 2-4 "Alynyl" refers to a straight-chain or branched alkynyl group containing 2-4 carbon atoms. It includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0158] The "alkynyl group" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0159] "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1-10 carbon atoms. 1-4 "Alkoxy" refers to alkyloxy groups containing 1-4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0160] The "alkoxy group" can be optionally substituted or unsubstituted. When substituted, the substituent, preferably one or more (preferably 1, 2, 3, or 4) groups, is independently selected from deuterium, halogen, cyano, nitro, azido, C... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0161] "Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is defined as described above, for example, "C 3-12 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C 3-8"Cycloalkoxy" refers to cycloalkyloxy groups containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0162] The "cycloalkoxy" group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C64, halogen, cycloalkoxy ... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0163] "Heterocyclic group" refers to -O-heterocyclic group, where the definition of heterocyclic group is as described above. Heterocyclic group oxygen groups include, but are not limited to, azirrocyclobutyroxy, oxocyclobutyroxy, azirrocyclopentyloxy, nitrogen, oxocyclohexyloxy, etc.

[0164] The "heterocyclic group" can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 -C 0-8 Alkyl-OR 13 -C 0-8 Alkyl-C(O)OR 13 -C 0-8 Alkyl-C(O)R 14 -C 0-8 Alkyl-OC(O)R 14 -C 0-8 Alkyl-NR 15 R 16 -C 0-8 Alkyl-C (=NR) 15 )R 14 -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 -C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 The substituents are replaced by the substituents.

[0165] “C 1-10 "alkylyl" refers to C 1-10 The monovalent group remaining after removing the hydroxyl group from an alkyl acid is usually also represented by "C". 0-9 "alkyl-C(O)-", for example, "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionyl; "C3 alkyl-C(O)-" refers to butyryl or isobutyryl.

[0166] “C 1-4 " refers to "C" 1-4 Alkyl", "C" 0-4 " refers to "C" 0-4 Alkyl", "C" 1-8 "Refers to C" 1-8 Alkyl, "C 0-8 "Refers to C" 0-8 Alkyl groups, as defined above.

[0167] -C 0-8 Alkyl-S(O) r R 12 "Referring to -S(O)" r R 12 The sulfur atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0168] -C 0-8 Alkyl-OR 13 "referring to -OR" 13 The oxygen atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0169] -C 0-8 Alkyl-C(O)OR 13 "Refers to -C(O)OR 13 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0170] -C 0-8 Alkyl-C(O)R 14 "Referring to -C(O)R" 14 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0171] -C 0-8 Alkyl-OC(O)R 14 "Refers to -OC(O)R 14 The oxygen atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0172] -C 0-8 Alkyl-NR 15 R 16 "Referring to -NR" 15 R 16 The nitrogen atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0173] -C 0-8 Alkyl-C (=NR) 15 )R 14 "Refers to -C(=NR)" 15 )R 14 The carbon atom in C is attached to C 0-8 On alkyl groups, C0-8 The definition of alkyl is as described above.

[0174] -C 0-8 Alkyl-N(R) 15 )-C(=NR 16 )R 14 "Referring to -N(R)" 15 )-C(=NR 16 )R 14 The nitrogen atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0175] -C 0-8 Alkyl-C(O)NR 15 R 16 "Refers to -C(O)NR" 15 R 16 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0176] -C 0-8 Alkyl-N(R) 15 )-C(O)R 14 "Referring to -N(R)" 15 )-C(O)R 14 The nitrogen atom in C is attached to C 0-8 On alkyl groups, C 0-8 The definition of alkyl is as described above.

[0177] "Hydrogen replaces C" 1-10 "Alkyl" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atoms are optionally replaced by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl (-CHF2), dichloromethyl (-CHCl2), dibromomethyl (-CHBr2), trifluoromethyl (-CF3), trichloromethyl (-CCl3), tribromomethyl (-CBr3), etc.

[0178] "Hydrogen replaces C" 1-10 "Alkoxy" refers to 1-10 carbon alkoxy groups on an alkyl group, where the hydrogen atom is optionally replaced by a fluorine, chlorine, bromine, or iodine atom. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0179] "Deuterium replaces C" 1-10 "Alkyl" refers to a 1-10 carbon alkyl group on an alkyl group in which the hydrogen atoms are optionally replaced by deuterium atoms. This includes, but is not limited to, monodeuterylmethyl (-CH2D), dideuterylmethyl (-CHD2), trideuterylmethyl (-CD3), etc.

[0180] "Deuterium replaces C" 1-10"Alkoxy" refers to a 1-10 carbon alkyl group on an alkyl group in which the hydrogen atom is optionally replaced by a deuterium atom. This includes, but is not limited to, monodeuteroxy, dideuteroxy, trideuteroxy, etc.

[0181] "Halogen" refers to fluorine, chlorine, bromine, or iodine. "EtOAc" refers to ethyl acetate. "PE" refers to petroleum ether. "DMF" refers to dimethylformamide.

[0182] "Optional" or "optionally" means that the event or environment described below may but does not have to occur. This description includes the possibility that the event or environment may or may not occur, that is, it includes both substituted and unsubstituted cases. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0183] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, conforming to the valence bond theory in chemistry, and that a person skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0184] Stereoisomers, also known as cis-trans isomers, are isomers formed by different spatial arrangements of atoms in a molecule. They can be classified into two main categories: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers resulting from bond length, bond angle, the presence of double bonds, or rings within the molecule are called configurational stereo-isomers. Configurational stereo-isomers are further divided into two categories. Those resulting from the inability of single bonds in double bonds or cyclic carbon atoms to rotate freely are called geometrical isomers, also known as cis-trans isomers, and have two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. If the compounds of this invention contain double bonds, unless otherwise specified, this can be understood as containing E and / or Z-type isomers. Stereoisomers with different optical rotation properties due to the lack of antiaxial symmetry in the molecule are called optical isomers, and are classified into R and S configurations. In this invention, unless otherwise specified, "stereoisomers" can be understood to include one or more of the enantiomers, configuration isomers, and conformational isomers mentioned above.

[0185] In this invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt or base addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0186] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0187] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0188] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (MeOH-d4), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0189] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0190] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0191] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0192] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0193] I. Preparation of intermediates

[0194] Intermediate A1: N 1 N 1 -dimethyl-N 2 Preparation of 1,2-(methyl-d3)ethane-1,2-diamine

[0195]

[0196] Add deuterated methylamine hydrochloride (4.9 g, 69.43 mmol) and water (5 mL) to a round-bottom flask, and cool the solution to -12 °C. Dissolve sodium hydroxide (2.78 g, 0.07 mmol) in water (4 mL) and add it dropwise to the round-bottom flask. Stir the mixture at -12 °C for 15 minutes. Then add an aqueous solution (4 mL) of 2-chloro-N,N-dimethylethane-1-amine hydrochloride (1 g, 6.94 mmol). Stir the reaction mixture at room temperature for 4 hours. Cool to 0 °C. Dissolve sodium hydroxide (2.9 g, 0.07 mmol) in water (10 mL) and add it dropwise to the round-bottom flask. Extract the mixture with dichloromethane (3 x 7 mL), dry the organic phase to anhydrous sodium sulfate, and distill under reduced pressure at low temperature to obtain N. 1 N 1 -dimethyl-N 2 -(methyl-d3)ethane-1,2-diamine is used directly in the next reaction.

[0197] Preparation of intermediate A2: 2-((methyl-d3)amino)ethane-1-ol hydrochloric acid

[0198]

[0199] Step 1: Synthesis of tert-butyl N-(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate

[0200]

[0201] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (5.3 g, 32.87 mmol) in dichloromethane (80 mL), imidazole (3.36 g, 49.31 mmol) and 4-(dimethylamino)pyridine (0.6 g, 4.91 mmol) were added at room temperature. The mixture was stirred at room temperature for 5 minutes. Then, a solution of dichlorodimethyl(2-methylpropyl-2-yl)silane (5.45 g, 36.16 mmol) in dichloromethane (20 mL) was slowly added dropwise to the mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water and dichloromethane were added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give tert-butyl N-(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (7.5 g, yield: 82%).

[0202] 1 H NMR (CDCl3) δ4.78 (s, 1H), 3.60 (t, J = 5.2Hz, 2H), 3.16 (q, J = 5.4Hz, 2H), 1.39 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H).

[0203] Step 2: Synthesis of tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl-d3)carbamate

[0204]

[0205] At 0 °C, sodium hydroxide (1.57 g, 39.20 mmol) was slowly added to a solution of tert-butyl N-(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (7.2 g, 26.13 mmol) in N,N-dimethylformamide (100 mL). After stirring for 30 minutes, deuterated iodomethane (1.8 mL, 28.75 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 minutes. The mixture was extracted with water and dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl-d3)carbamate (5.5 g, yield: 71%).

[0206] 1 H NMR (CDCl3) δ3.65 (d, J = 10.3 Hz, 2H), 3.24 (d, J = 7.4 Hz, 2H), 1.40 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H).

[0207] Step 3: Synthesis of 2-((methyl-d3)amino)ethane-1-ol hydrochloric acid

[0208]

[0209] At room temperature, 14 mL of 4 N dioxane hydrochloride was added to a 15 mL solution of tert-butyl(2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl-d3)carbamate (5.5 g, 18.80 mmol) in tetrahydrofuran. The mixture was stirred at room temperature for 3 hours. The reaction solution was distilled under reduced pressure to give 1.5 g of 2-((methyl-d3)amino)ethane-1-ol hydrochloride.

[0210] Intermediate A3: N 1 -(4-Methoxybenzyl)-N 2 N 2 Preparation of 1,2-dimethylethane-1,2-diamine

[0211]

[0212] N 1 N 1- Dimethylethane-1,2-diamine (10 g, 113.4 mmol) and 4-methoxybenzaldehyde (18.5 g, 136.1 mmol) were dissolved in dichloromethane (10 mL). Acetic acid (0.65 mL, 11.6 mmol) and sodium acetylborohydride (35 g, 170.1 mmol) were added to the above solution. The reaction was stirred at room temperature for 18 hours. The layers were separated by ethyl acetate and water, and the organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether:ethyl acetate = 4:1] to give N. 1 -(4-Methoxybenzyl)-N 2 N 2 -Dimethylethane-1,2-diamine (16 g, yield: 67%). ESI-MS: 209.0 [M+1] + .

[0213] Preparation of Intermediate A4: 1-((2R,4S)-4-fluoropyrrolidone-2-yl)-N,N-dimethylmethylamine

[0214]

[0215] Step 1: Synthesis of 1-(tert-butyl)-2-methyl(2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid ester

[0216]

[0217] Under ice bath conditions, N,N-diethyl-1,1,1-trifluoro-14-thioalkylamine (19.7 g, 122.3 mmol) was added to a solution of 1-(tert-butyl)-2-methyl(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid ester (15.0 g, 61.1 mmol) in dichloromethane (100 mL). The mixture was stirred under ice bath conditions for 30 min, then stirred at 30 °C for 2 h. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate solution, quenched, and then extracted with dichloromethane to separate the layers. The organic phase was concentrated and separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 1-(tert-butyl)-2-methyl(2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid ester (8.20 g, yield: 54.23%).

[0218] 1H NMR(DMSO-d6)δ5.31(dt,J=52.6,3.5Hz,1H),4.34–4.21(m,1H),3.72–3.61(m,4H) ,3.58–3.42(m,1H),2.61–2.52(m,1H),2.22–2.00(m,1H),1.37(d,J=24.0Hz,9H).

[0219] Step 2: Synthesis of (2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid

[0220]

[0221] At room temperature, lithium hydroxide (6.9 g, 165.8 mmol) was added to a solution of 1-(tert-butyl)-2-methyl(2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid ester (8.2 g, 33.1 mmol) in methanol / tetrahydrofuran / water (20 mL / 20 mL / 20 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the pH was adjusted to 4–5 with concentrated hydrochloric acid. The layers were then extracted with dichloromethane. The organic phase was concentrated to give (2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (8.0 g, yield: 103.4%). ESI-MS: 232.0 [M-1] + .

[0222] Step 3: Synthesis of tert-butyl(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid ester

[0223]

[0224] A solution of borane-tetrahydrofuran (55.7 g, 55.7 mmol, 1 M) was added to a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (6.5 g, 27.8 mmol) in tetrahydrofuran (80 mL) under ice bath conditions. The mixture was stirred under ice bath conditions for 30 min, then at 75 °C for 1 h. After the reaction was complete, the reaction solution was slowly poured into saturated ice water to quench the reaction, and then extracted with dichloromethane to separate the layers. The organic phase was concentrated and separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-70%] to tert-butyl(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid ester (5.1 g, yield: 83.4%). ESI-MS: 164.2 [M+1-56] + .

[0225] Step 4: Synthesis of tert-butyl(2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester

[0226]

[0227] Under ice bath conditions, N,N-diisopropylethylamine (8.1 g, 62.9 mmol) and ethylsulfonyl chloride (4.0 g, 31.5 mmol) were added to a solution of tert-butyl(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid ester (4.6 g, 20.9 mmol) in dichloromethane (50 mL). The mixture was stirred under ice bath conditions for 30 min. After the reaction was complete, the layers were extracted with dichloromethane and water. The organic phase was concentrated and separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give tert-butyl(2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester (5.2 g, yield: 79.6%). ESI-MS: 212.2 [M+1-100] + .

[0228] Step 5: Synthesis of tert-butyl(2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester

[0229]

[0230] In a sealed tube, a solution of tert-butyl(2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester (5.2 g, 16.7 mmol) and dimethylaminetetrahydrofuran (50 mL, 100.0 mmol, 2 M) was stirred at 80 °C for 3 hours. After the reaction was complete, the solution was concentrated and separated by rapid silica gel column chromatography [eluent: dichloromethanol / methanol: 0-10%] to give tert-butyl(2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester (3.0 g, yield: 72.9%). ESI-MS: 247.3 [M+1] + .

[0231] 1 H NMR(DMSO-d6)δ5.20(dt,J=53.4,3.7Hz,1H),3.91(s,1H),3.76–3.67(m,1H),3.32–3.21( s,1H),2.49–2.39(m,1H),2.33–2.19(m,2H),2.15(s,6H),2.10–1.97(m,1H),1.41(s,9H).

[0232] Step 6: Synthesis of 1-((2R,4S)-4-fluoropyrrolidine-2-yl)-N,N-dimethylmethylamine

[0233]

[0234] A solution of tert-butyl(2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylic acid ester (3.0 g, 12.2 mmol) and hydrochloric acid / 1,4-dioxane (50 mL, 200.0 mmol, 4 M) was stirred at room temperature for 3 hours. After the reaction was complete, the solution was concentrated to give 1-((2R,4S)-4-fluoropyrrolidine-2-yl)-N,N-dimethylmethylamine hydrochloride (3.0 g, yield: 77.3%). ESI-MS: 147.3 [M+1] + .

[0235] Intermediate B1: N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 Preparation of 1,4-methyl-2-nitrobenzene-1,4-diamine

[0236]

[0237] 4-Fluoro-2-methoxy-5-nitroaniline (1.86 g, 10.0 mmol) was dissolved in 10 mL of N,N-dimethylformamide. N was added to the solution at room temperature. 1 N 1 N 2 -Trimethylethane-1,2-diamine (1.53 g, 15.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol). The reaction was stirred at 85 °C for 3 hours. Water was added to the solution, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, the solution was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to give N. 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 1,4-Methyl-2-nitrobenzene-1,4-diamine (2.5 g, yield: 93%). ESI-MS: 269.0 [M+1] + .

[0238] Preparation of Intermediate B2: N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide

[0239]

[0240] N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 11,4-Methyl-2-nitrobenzene-1,4-diamine (2.68 g, 10 mmol) and formic acid (20 mL) were added to a reaction flask, and the reaction mixture was stirred at 100 °C for 2 hours. Formic acid was removed by vacuum distillation, and the residue was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to give N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)formamide (2.89 g, yield: 93%). ESI-MS: 296.0 [M+1] + .

[0241] Intermediate B3: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 Preparation of 1,4-methyl-2-nitrobenzene-1,4-diamine

[0242]

[0243] Step 1: Synthesis of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene

[0244]

[0245] Sodium carbonate (20.2 g, 190.9 mmol) was added to a solution of 5-fluoro-2-nitrophenol (10 g, 63.6 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 90 °C, and sodium 2-chloro-2,2-difluoroacetate (34.0 g, 222.8 mmol) was added in portions, followed by stirring for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and separated by column chromatography [eluent: petroleum ether / ethyl acetate: 0-10%] to give 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, yield: 78%).

[0246] 1 H NMR (CDCl3) δ7.96 (dd, J = 9.1, 5.6 Hz, 1H), 7.11–6.97 (m, 2H), 6.57 (t, J = 72.4 Hz, 1H).

[0247] Step 2: Synthesis of 2-(difluoromethoxy)-4-fluoroaniline

[0248]

[0249] In an ethanolic solution of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, 49.7 mmol), 10% palladium on carbon (1.0 g) was added. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered and distilled under reduced pressure to give 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, yield: 86%). ESI-MS: 178.1 [M+1] + .

[0250] Step 3: Synthesis of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline

[0251]

[0252] Potassium nitrate (5.1 g, 50.3 mmol) was added in portions to a solution of 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 45.7 mmol) in 40 mL of sulfuric acid under ice bath conditions. The reaction was stirred under ice bath conditions for 0.5 h, then stirred at room temperature for 2 h. The reaction mixture was slowly poured into ice water (500 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-15%] to give 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (8.0 g, yield: 77%).

[0253] 1 H NMR (CDCl3) δ7.49 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 10.9 Hz, 1H), 6.61 (t, J = 72.1 Hz, 1H), 4.06 (s, 2H).

[0254] Step 4: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 Synthesis of 1,4-methyl-2-nitrobenzene-1,4-diamine

[0255]

[0256] In a solution of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (1.0 g, 4.5 mmol) in acetonitrile (30 mL), N was added 1 N 1 N 2 -Trimethylethane-1,2-diamine (690 mg, 6.7 mmol) and potassium carbonate (1.2 g, 9.0 mmol). The reaction mixture was stirred at 80 °C for 3 hours. After removing the solvent, [dichloromethane:methanol = 10:1] was separated by silica gel column chromatography to give 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 11,4-Methyl-2-nitrobenzene-1,4-diamine (1.25 g, yield: 83%). ESI-MS: 305.2 [M+1] + .

[0257] Intermediates B4 and B5 were prepared using the same method as intermediate B3: sodium 2-chloro-2,2-difluoroacetate in the first step was replaced with deuterated iodomethane, iodoethane, or isopropyl iodoethane, and the reaction conditions were changed to stirring at 37°C for 18 hours; the remaining steps were the same. Intermediate B6 was prepared using the same method as intermediate B3, from steps one to three.

[0258]

[0259]

[0260] Intermediate B7: N 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N 1 Preparation of 1,4-methyl-2-nitrobenzene-1,4-diamine

[0261]

[0262] Step 1: Synthesis of tert-butyl (4-fluoro-2-methoxy-5-nitrobenzene) carbamate

[0263]

[0264] 4-Fluoro-2-methoxy-5-nitroaniline (1 g, 5.4 mmol) was dissolved in 1,4-dioxane (30 mL), and di-tert-butyl dicarbonate (2.2 g, 10.8 mmol) was added. The mixture was stirred overnight at 120 °C. The solvent was removed, and the residue was subjected to column chromatography to give tert-butyl(4-fluoro-2-methoxy-5-nitrobenzene) carbamate (1.3 g, yield: 84.4%). ESI-MS: 287.2 [M+1] + .

[0265] Step 2: Synthesis of tert-butyl (4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)carbamate

[0266]

[0267] In a solution of tert-butyl(4-fluoro-2-methoxy-5-nitrobenzene)carbamate (328 mg, 1.15 mmol) in 1,4-dioxane (10 mL), 2-(methylamino)ethane-1-ol (129 mg, 1.72 mmol) and N,N-diisopropylethylamine (296 mg, 2.3 mmol) were added. The reaction mixture was stirred at 120 °C for 1 hour. After solvent removal, silica gel column chromatography [dichloromethane:methanol = 10:1] was used to separate tert-butyl(4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)carbamate (390 mg, yield: 90.7%). ESI-MS: 342.0 [M+1] + .

[0268] Step 3: Synthesis of 2-((4-((tert-butoxycarbonyl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate

[0269]

[0270] A solution of tert-butyl(4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)carbamate (390 mg, 1.14 mmol) in dichloromethane (10 mL) was cooled to 0 °C, and N,N-diisopropylethylamine (443 mg, 3.4 mmol) and methanesulfonyl chloride (157 mg, 1.37 mmol) were added. The reaction mixture was stirred at 0 °C for 0.5 h. After removing the solvent, silica gel column chromatography [dichloromethane:methanol = 10:1] was used to separate the esters to 2-((4-((tert-butoxycarbonyl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate (480 mg, yield: 100%). ESI-MS: 420.0 [M+1] + .

[0271] Step 4: Synthesis of tert-butyl(4-((2-(di(methyl-d3)amine)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)carbamate

[0272]

[0273] 2-((4-((tert-butoxycarbonyl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate (480 mg, 1.14 mmol), acetonitrile (8 mL), potassium carbonate (474.5 mg, 3.4 mmol), and di(methyl-d3)amine hydrochloride (501 mg, 5.72 mmol) were added to a sealed tube. The reaction mixture was stirred at 60 °C for 5 hours. After removing the solvent, silica gel column chromatography [dichloromethane:methanol = 10:1] was used to separate tert-butyl(4-((2-(di(methyl-d3)amine)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate (293 mg, yield: 68.1%). ESI-MS: 375.2 [M+1] + .

[0274] Step 5: N 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N 1 Synthesis of 1,4-methyl-2-nitrobenzene-1,4-diamine

[0275]

[0276] In a solution of tert-butyl(4-((2-(di(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene)carbamate (293 mg, 0.78 mmol) in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After removing the solvent, N was obtained. 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N 1 1,4-Methyl-2-nitrobenzene-1,4-diamine (180 mg, yield: 83.8%). ESI-MS: 275.1 [M+1] + .

[0277] Intermediate B8: N 1 Preparation of 1,4-(2-(dimethylamino)ethyl)-5-((4-methoxybenzyl)oxy)-2-nitrobenzene-1,4-diamine

[0278]

[0279] Step 1: Synthesis of 2-amino-5-fluoro-4-nitrophenol

[0280]

[0281] 2-Amino-5-fluorophenol (5.08 g, 39.96 mmol) was dissolved in dichloromethane and cooled to -10 °C. A mixture of 63% nitric acid (4.44 g, 47.96 mmol) and 98% sulfuric acid (10 mL, 179.85 mmol) was added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at -10 °C for 2 hours. The reaction was quenched with saturated sodium sulfate solution, diluted with ethyl acetate, and the layers were separated. The organic phase was washed twice with water and once with saturated brine. The organic phase was dried, and the solvent was removed by vacuum distillation. The residue was separated by column chromatography to obtain 2-amino-5-fluoro-4-nitrophenol (1.4 g, yield: 18.93%). ESI-MS: 190.0 [M+NH4] + .

[0282] Step 2: Synthesis of N-(4-fluoro-2-hydroxy-5-nitrophenyl)acetamide

[0283]

[0284] 2-Amino-5-fluoro-4-nitrophenol (500 mg, 2.91 mmol) and acetic anhydride (20 mL) were added to a round-bottom flask, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water, the solid was collected by filtration and dried to give N-(4-fluoro-2-hydroxy-5-nitrophenyl)acetamide (580 mg, yield: 88.57%). ESI-MS: 232.0 [M+NH4] + .

[0285] Step 3: Synthesis of N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide

[0286]

[0287] N-(4-fluoro-2-hydroxy-5-nitrophenyl)acetamide (580 mg, 2.71 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (748.6 mg, 5.42 mmol) and p-methoxybenzyl chloride (0.55 mL, 4.06 mmol) were added. The reaction mixture was stirred at 50 °C for 2 hours until the reaction was complete. The reaction mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (720 mg, yield: 43.74%). ESI-MS: 352.0 [M+NH4] + .

[0288] Step 4: Synthesis of N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide

[0289]

[0290] In a solution of N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (720 mg, 2.15 mmol) in 1,4-dioxane (30 mL), N 1 N 1 N 2 Trimethylethane-1,2-diamine (0.65 mL, 4.31 mmol) and diisopropylethylamine (0.65 mL, 4.31 mmol) were reacted. The reaction mixture was stirred at 50 °C for 2 hours. After solvent removal, [dichloromethane:methanol = 10:1] was separated by silica gel column chromatography to give N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (620 mg, yield: 53%). ESI-MS: 417.2 [M+1] + .

[0291] Step 5: N 1 Synthesis of 1,4-(2-(dimethylamino)ethyl)-5-((4-methoxybenzyl)oxy)-2-nitrobenzene-1,4-diamine

[0292]

[0293] N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (620 mg, 1.49 mmol) was dissolved in ethanol (20 mL) and water (5 mL), and sodium hydroxide (297.73 mg, 7.44 mmol) was added. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography to obtain N... 1 1,4-Nitrophenyl-1,4-diamine (150 mg, yield: 24.9%). ESI-MS: 361.2 [M+1] + .

[0294] Intermediate B9: N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Preparation of 2,5-methyl-3-nitropyridine-2,5-diamine

[0295]

[0296] Step 1: Synthesis of 6-bromo-2-methoxy-3-nitropyridine

[0297]

[0298] Sodium methoxide (5.3 g, 78.0 mmol) was added to a solution of 2,6-dibromo-3-nitropyridine (20 g, 70.9 mmol) in tetrahydrofuran (300 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and separated by column chromatography [petroleum ether:ethyl acetate = 5:1] to give 6-bromo-2-methoxy-3-nitropyridine (13.9 g, yield: 85%). ESI-MS: 217.1 [M-15] + .

[0299] Step 2: Synthesis of 6-bromo-2-methoxypyridine-3-amine

[0300]

[0301] Iron powder (26.9 g, 480.8 mmol) and ammonium chloride (25.9 g, 480.8 mmol) were added to a solution of 6-bromo-2-methoxy-3-nitropyridine (13.9 g, 60.1 mmol) in ethanol / water (2:1). The reaction was stirred at approximately 90 °C for 3 hours. The layers were separated by dichloromethane and water. The organic phase was concentrated and separated by column chromatography (petroleum ether: ethyl acetate (3:1)) to give 6-bromo-2-methoxypyridine-3-amine (9.1 g, yield: 75%). ESI-MS: 203.1 [M+1] + .

[0302] 1 H NMR (DMSO-d6) δ6.89 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.10 (s, 2H), 3.84 (s, 3H).

[0303] Step 3: Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)acetamide

[0304]

[0305] In an ice bath, triethylamine (6.7 g, 67.2 mmol) and acetyl chloride (3.8 g, 49.2 mmol) were added to a solution of 6-bromo-2-methoxypyridin-3-amine (9.1 g, 44.8 mmol) in 200 mL of dichloromethane. The reaction was stirred in an ice bath for 1 hour. The layers were separated by dichloromethane and water, and the organic phase was concentrated and separated by column chromatography [petroleum ether: ethyl acetate = 5:1] to give N-(6-bromo-2-methoxypyridin-3-yl)acetamide (9.5 g, yield: 86%). This was used directly for the next step.

[0306] Step 4: Synthesis of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide

[0307]

[0308] Concentrated nitric acid (65%, 46.6 mmol) was added to a solution of N-(6-bromo-2-methoxypyridin-3-yl)acetamide (9.5 g, 38.9 mmol) in 80 mL of trifluoroacetic anhydride under ice bath conditions. The reaction was stirred under ice bath conditions for 1 hour. The reaction solution was slowly poured into ice water and stirred for 1 hour, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was dried to give N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (11.5 g, yield: 100%). ESI-MS: 290.1 ​​[M+1] + .

[0309] 1 H NMR(DMSO-d6)δ9.90(s,1H),9.12(s,1H),4.06(s,3H),2.16(s,3H).

[0310] Step 5 (Intermediate B9-1): Synthesis of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide

[0311]

[0312] In a solution of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 3.4 mmol) in acetonitrile (20 mL), N was added. 1 N 1 N 2 -Trimethylethane-1,2-diamine (520 mg, 5.1 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After solvent removal, the mixture was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to give N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (756 mg, yield: 71%). ESI-MS: 312.3 [M+1] + .

[0313] Step 6: N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Synthesis of methyl-3-nitropyridine-2,5-diamine

[0314]

[0315] In a methanol (10 mL) solution of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (756 mg, 2.4 mmol), concentrated hydrochloric acid (37%, 1.5 mL, 18 mmol) was added. The reaction was stirred at 60 °C for 5 hours. The mixture was separated into layers with saturated sodium bicarbonate solution and dichloromethane. After concentration of the organic phase, N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide was obtained. 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 2,5-Methyl-3-nitropyridine-2,5-diamine (645 mg, yield: 100%). ESI-MS: 270.3 [M+1] + .

[0316] Intermediates B10-1 to B14-1 were prepared using the same method as intermediate B9-1.

[0317]

[0318] Intermediates B10 to B14 were prepared using the same method as intermediate B9.

[0319]

[0320] Preparation of intermediate B15: 2-cyclopropoxy-4-fluoro-5-nitroaniline

[0321]

[0322] Step 1: Synthesis of 2-cyclopropoxy-4-fluoroaniline

[0323]

[0324] Cyclopropanol (1.46 g, 25.14 mmol) and cesium carbonate (8.19 g, 25.14 mmol) were added to a tetrahydrofuran (80 mL) solution of 2,4-difluoro-1-nitrobenzene (4.0 g, 25.14 mmol). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the solution was diluted with water and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain 2-cyclopropoxy-4-fluoro-1-nitrobenzene. The crude product was dissolved in methanol (120 mL), and water (30 mL), iron powder (7.0 g, 125.70 mmol), and ammonium chloride (10.86 g, 201.12 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the diatomaceous earth was filtered, and the resulting solution was separated into layers with ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-cyclopropoxy-4-fluoroaniline (2.68 g, yield: 64%). ESI-MS: 168.0 [M+1] + .

[0325] Step 2: Synthesis of N-(2-cyclopropoxy-4-fluorophenyl)acetamide

[0326]

[0327] At 0 °C, N,N-diisopropylethylamine (1.93 mL, 11.66 mmol) and acetyl chloride (0.61 mL, 8.55 mmol) were added to a solution of 2-cyclopropoxy-4-fluoroaniline (1.3 g, 7.77 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, the solution was diluted with dichloromethane and saturated sodium bicarbonate aqueous solution. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the solvent, and N-(2-cyclopropoxy-4-fluorophenyl)acetamide (1.55 g, yield: 95%) was obtained. ESI-MS: 210.0 [M+1] + .

[0328] Step 3: Synthesis of N-(2-cyclopropoxy-4-fluoro-5-nitrophenyl)acetamide

[0329]

[0330] N-(2-cyclopropoxy-4-fluorophenyl)acetamide (1.55 g, 7.38 mmol) and trifluoroacetic anhydride (16 mL) were added to a 250 mL single-necked flask. The mixture was cooled to -10 °C in an ice-salt bath, and concentrated nitric acid (0.8 mL, 11.8 mmol) was added dropwise while maintaining the temperature below -5 °C. After the addition was complete, the mixture was stirred at -10 °C for 1.5 hours. The reaction mixture was slowly poured into 90 mL of ice water, causing a solid to precipitate. The solid was filtered, and the filter cake was dried to obtain the crude product. The crude product was separated by column chromatography to obtain N-(2-cyclopropoxy-4-fluoro-5-nitrophenyl)acetamide (621 mg, yield: 33%). ESI-MS: 255.0 [M+1] + .

[0331] Step 4: Synthesis of 2-cyclopropoxy-4-fluoro-5-nitroaniline

[0332]

[0333] Concentrated hydrochloric acid (1 mL) was added to a methanol (10 mL) solution of N-(2-cyclopropoxy-4-fluoro-5-nitrophenyl)acetamide (138 mg, 0.54 mmol). The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the solvent was removed, dichloromethane (10 mL) was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, and the organic phases were combined. The resulting organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to obtain 2-cyclopropoxy-4-fluoro-5-nitroaniline (85 mg, yield: 73%). ESI-MS: 213.0 [M+1] + .

[0334] Preparation of intermediate C1: 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0335]

[0336] Step 1: Synthesis of 1-(tert-butyl)3-ethyl-2-(3-nitropyridin-2-yl)malonate

[0337]

[0338] 44.52 g (236.5 mmol) of tert-butyl ethyl malonate was slowly added dropwise to a suspension of sodium hydride (9.46 g, 236.5 mmol) in tetrahydrofuran (200 mL) at 0 °C. The mixture was stirred at room temperature for 0.5 h, and then 2-chloro-3-nitropyridine (25.0 g, 157.7 mmol) was added to the mixture. The reaction mixture was stirred at 60 °C for 1.5 h. After the reaction was complete, it was cooled to 0 °C, and the reaction was quenched by slowly adding a saturated ammonium chloride solution. The mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 1-(tert-butyl)-3-ethyl-2-(3-nitropyridine-2-yl)malonate (32.7 g, yield: 66.8%). ESI-MS: 255.0 [M-55] + .

[0339] Step 2: Synthesis of ethyl 2-(3-nitropyridin-2-yl)acetic acid ester

[0340]

[0341] Trifluoroacetic acid (18.8 mL, 252.9 mmol) was added to 1-(tert-butyl)-3-ethyl-2-(3-nitropyridin-2-yl)malonate (32.7 g, 84.3 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction solution was cooled to room temperature, and the trifluoroacetic acid was removed by vacuum distillation. The residue was added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Vacuum distillation yielded ethyl-2-(3-nitropyridin-2-yl)acetic acid ester (17.7 g, yield: 91.9%). ESI-MS: 211.0 [M+1] + .

[0342] Step 3: Synthesis of ethyl 2-methyl-2-(3-nitropyridin-2-yl)propionate

[0343]

[0344] Iodimethane (6.25 g, 44 mmol) and 18-crown ether-6 (0.39 g, 1.47 mmol) were added to a solution of ethyl 2-(3-nitropyridin-2-yl)acetate (3.1 g, 14.7 mmol) in N,N-dimethylformamide (30 mL) at 0 °C. Sodium hydride (1.2 g, 29.4 mmol) was then slowly added. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was then distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give ethyl 2-methyl-2-(3-nitropyridin-2-yl)propionate (3.2 g, yield: 91%). ESI-MS: 239.0 [M+1] + .

[0345] Step 4: Synthesis of 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0346]

[0347] Ammonium formate (3.4 g, 53.7 mmol) and 10% palladium on carbon (300 mg) were added to a solution of ethyl 2-methyl-2-(3-nitropyridin-2-yl)propionate (3.2 g, 13.4 mmol) in ethanol (20 mL). The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressure to give crude 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.72 g, yield: 79%), which was used directly in the next step. ESI-MS: 163.0 [M+1] + .

[0348] Step 5: Synthesis of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0349]

[0350] 1.22 g (7.53 mmol) of 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (4 mL, 2.5 M) was added dropwise. The mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 1.2 g (100% yield) of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. ESI-MS: 149.0 [M+1]+ .

[0351] Preparation of intermediate C2: 1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)

[0352]

[0353] Step 1: Synthesis of ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester

[0354]

[0355] 2-(3-nitropyridin-2-yl)acetate (2.18 g, 9.85 mmol) was dissolved in dimethyl sulfoxide (50 mL), and then diphenyl(vinyl)sulfonium trifluoromethanesulfonate (4.28 g, 11.82 mmol) was added. The mixture was stirred at room temperature for 2 minutes, and then 2,3,4,6,7,8,9,10-octahydropyrimidine[1,2-a]azapyrrolidone (4.42 mL, 29.56 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was separated by column chromatography to give ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester (2.05 g, yield: 82.79%), ESI-MS: 236.9 [M+1]. + .

[0356] Step 2: Synthesis of ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylic acid ester

[0357]

[0358] To a solution of ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester (2.05 g, 8.24 mmol) in ethanol (20 mL), 10% palladium on carbon (100 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylic acid ester (1.70 g, yield: 100%), which was used directly in the next reaction. ESI-MS: 206.9 [M+1] + .

[0359] Step 3: Synthesis of spiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0360]

[0361] To a solution of ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylic acid (1.7 g, 8.24 mmol) in ethanol (20 mL), 0.5 mL of 36% hydrochloric acid was added, and the mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was neutralized with sodium hydroxide solution, washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give spiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (0.4 g, yield: 28.8%), ESI-MS: 160.9 [M+1]. + .

[0362] Step 4: Synthesis of 1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)

[0363]

[0364] Spiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (0.4 g, 2.48 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (3 mL, 2.5 M) was added dropwise. The mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) (327 mg, yield: 89.6%). ESI-MS: 147.0 [M+1] + .

[0365] Preparation of intermediate C3: 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0366]

[0367] Step 1: Synthesis of spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0368]

[0369] Sodium hydride (3.0 g, 74.5 mmol) and hexamethylphosphoric triamine (12 mL) were dissolved in anhydrous N,N-dimethylformamide (60 mL). 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4.0 g, 29.8 mmol) and 1,3-diiodopropane (8.8 g, 29.8 mmol) were added to the reaction solution. The reaction solution was stirred at 0 °C under nitrogen protection for 1 hour. After the reaction was complete, the reaction solution was separated into layers with ethyl acetate (100 mL) and saturated brine (100 mL). The organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was separated by rapid silica gel column chromatography [petroleum ether / ethyl acetate = 3:1] to give spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (1.2 g, 23%). ESI-MS: 175.0 [M+1] + .

[0370] Step 2: Synthesis of 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0371]

[0372] Spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (240 mg, 1.38 mmol) was dissolved in tetrahydrofuran (10 mL). Borane dimethyl sulfide solution (1.4 mL, 14 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection until the reaction was complete. The reaction mixture was separated into layers with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was separated by rapid silica gel column chromatography [petroleum ether / ethyl acetate = 2:1] to obtain 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine (210 mg, 95%). ESI-MS: 161.0 [M+1] + .

[0373] Preparation of intermediate C4: 5'-(1-methyl-1H-pyrazole-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0374]

[0375] Step 1: Synthesis of 5'-bromo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0376]

[0377] 1',2'-Dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (170 mg, 1.06 mmol) was dissolved in acetonitrile (10 mL), and N-bromosuccinimide (188.8 mg, 1.06 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was separated by rapid silica gel column chromatography to obtain 5'-bromo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (161 mg, 62.8%). ESI-MS: 239.1, 241.1 [M+1] + .

[0378] Step 2: Synthesis of 5'-(1-methyl-1H-pyrazole-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0379]

[0380] Add 5'-bromo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (161 mg, 0.67 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (280.2 mg, 1.35 mmol), potassium phosphate (428.8 mg, 2.02 mmol), tricyclohexylphosphine (75.5 mg, 0.27 mmol), palladium acetate (30.2 mg, 0.14 mmol), and toluene (30 mL) to the reaction flask. Purge the mixture three times with nitrogen, and heat to 110 °C with stirring for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was then separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 5'-(1-methyl-1H-pyrazole-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (70 mg, yield: 40.2%). ESI-MS: 241.0 [M+1] + .

[0381] Preparation of intermediate C5: 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0382]

[0383] Step 1: Synthesis of 2-iodo-6-methyl-N-(2-methylallyl)pyridine-3-amine

[0384]

[0385] Potassium tert-butoxide (1.14 g, 10.2 mmol) was added to a tetrahydrofuran (40 mL) solution of 2-iodo-6-methylpyridin-3-amine (2 g, 8.5 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (1.27 g, 9.4 mmol) was slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 2-iodo-6-methyl-N-(2-methylallyl)pyridin-3-amine (1.46 g, yield: 59%). ESI-MS: 288.9 [M+1] + .

[0386] Step 2: Synthesis of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0387]

[0388] 2-Iodo-6-methyl-N-(2-methylallyl)pyridine-3-amine (1.46 g, 5 mmol), sodium formate (413 mg, 6 mmol), tetrabutylammonium chloride (1.67 g, 6 mmol), triethylamine (1.5 g, 15 mmol), palladium acetate (224 mg, 1 mmol), dimethyl sulfoxide (40 mL), and water (1.5 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, heated to 120 °C, and stirred for 1 hour under nitrogen protection. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (660 mg, yield: 81%). ESI-MS: 163.0 [M+1] + .

[0389] Preparation of intermediate C6: 5-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0390]

[0391] Step 1: Synthesis of 6-chloro-2-iodopyridin-3-amine

[0392]

[0393] N-iodosuccinimide (19.3 g, 85.6 mmol) was added to a solution of 6-chloropyridin-3-amine (10 g, 77.8 mmol) in N,N-dimethylformamide (150 mL) at room temperature. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 6-chloro-2-iodopyridin-3-amine (15.5 g, yield: 78.3%). ESI-MS: 254.8 [M+1] + .

[0394] Step 2: Synthesis of 6-chloro-2-iodo-N-(2-methylallyl)pyridine-3-amine

[0395]

[0396] Potassium tert-butoxide (8.2 g, 73.1 mmol) was added to a tetrahydrofuran (200 mL) solution of 15.5 g (60.9 mmol) of 6-chloro-2-iodopyridin-3-amine at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 9.9 g (73.1 mmol) of 3-bromo-2-methylprop-1-ene was slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 15.5 g (yield: 82.5%) of 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine. ESI-MS: 308.8 [M+1] + .

[0397] Step 3: Synthesis of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0398]

[0399] Add 6-chloro-2-iodo-N-(2-methylallyl)pyridine-3-amine (15.5 g, 50.2 mmol), sodium formate (4.2 g, 60.3 mmol), tetrabutylammonium chloride (16.8 g, 60.3 mmol), triethylamine (15.3 g, 150.7 mmol), palladium acetate (1.69 g, 7.5 mmol), dimethyl sulfoxide (200 mL), and water (6.7 mL) to the reaction flask. Purge the mixture three times with nitrogen, and heat to 120 °C with stirring for 1 hour under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was then separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (6.6 g, yield: 70.8%). ESI-MS: 183.1 [M+1] + .

[0400] Step 4: Synthesis of 5-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0401]

[0402] Add 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (450 mg, 2.5 mmol), cyclopropylboronic acid (1.1 g, 12.4 mmol), potassium phosphate (1.94 g, 9.1 mmol), tricyclohexylphosphine (138 mg, 0.5 mmol), palladium acetate (55 mg, 0.3 mmol), and toluene (30 mL) to a reaction flask. Purge the mixture three times with nitrogen, and heat to 110 °C with stirring for 6 hours under nitrogen protection. Filter the reaction mixture, wash the filtrate with water, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, distill under reduced pressure, and separate the crude product by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 5-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (152 mg, yield: 33.0%). ESI-MS: 189.0 [M+1] + .

[0403] Preparation of intermediate C7: 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0404]

[0405] Add 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (274 mg, 1.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (623.3 mg, 3.0 mmol), potassium phosphate (955.3 mg, 4.5 mmol), tricyclohexylphosphine (168.3 mg, 0.6 mmol), palladium acetate (67 mg, 0.3 mmol), and toluene (50 mL) to the reaction flask. Purge the mixture three times with nitrogen, and heat to 110 °C with stirring for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was then separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (125 mg, yield: 35.8%). ESI-MS: 229.0 [M+1] + .

[0406] Preparation of intermediate C8: 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0407]

[0408] Step 1: Synthesis of 6-bromo-2-iodopyridine-3-amine

[0409]

[0410] N-iodosuccinimide (2.70 g, 12.0 mmol) was added to a solution of 1.73 g (10 mmol) of 6-bromopyridin-3-amine in 50 mL of N,N-dimethylformamide at room temperature. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 6-bromo-2-iodopyridin-3-amine (2.1 g, yield: 66.4%). ESI-MS: 298.8, 300.8 [M+1] + .

[0411] Step 2: Synthesis of 6-bromo-2-iodo-N-(2-methylallyl)pyridine-3-amine

[0412]

[0413] Potassium tert-butoxide (8.4 mL, 8.4 mmol, 1 M / mL) was added to a tetrahydrofuran (50 mL) solution of 6-bromo-2-iodopyridin-3-amine (2.09 g, 7.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (1.04 g, 7.7 mmol) was slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 6-bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine (2.1 g, yield: 69.8%). ESI-MS: 352.8, 354.8 [M+1] + .

[0414] Step 3: Synthesis of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0415]

[0416] To a reaction flask, add 6-bromo-2-iodo-N-(2-methylallyl)pyridine-3-amine (2.1 g, 5.9 mmol), sodium formate (0.49 g, 7.1 mmol), tetrabutylammonium chloride (1.98 g, 7.1 mmol), triethylamine (1.8 g, 17.8 mmol), palladium acetate (0.2 g, 0.9 mmol), dimethyl sulfoxide (20 mL), and water (2 mL). Purge the mixture three times with nitrogen, and heat to 120 °C with stirring for 1 hour under nitrogen protection. Filter the reaction mixture, wash the filtrate with water, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, distill under reduced pressure, and separate the crude product by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.6 g, yield: 38.6%). ESI-MS: 226.9, 228.9 [M+1] + .

[0417] Preparation of intermediate C9: 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0418]

[0419] Step 1: Synthesis of 2-iodo-N-(2-methylallyl)-6-(trifluoromethyl)pyridine-3-amine

[0420]

[0421] Potassium tert-butoxide (933 mg, 8.33 mmol) was added to a tetrahydrofuran (30 mL) solution of 2-iodo-6-(trifluoromethyl)pyridine-3-amine (2 g, 6.94 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (1.17 g, 8.33 mmol) was slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 2-iodo-N-(2-methylallyl)-6-(trifluoromethyl)pyridine-3-amine (888 mg, yield: 37%). ESI-MS: 342.9 [M+1] + .

[0422] Step 2: Synthesis of 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0423]

[0424] Add 2-iodo-N-(2-methylallyl)-6-(trifluoromethyl)pyridine-3-amine (888 mg, 2.6 mmol), sodium formate (212 mg, 3.1 mmol), tetrabutylammonium chloride (862 mg, 3.1 mmol), triethylamine (788 mg, 7.8 mmol), palladium acetate (116 mg, 0.52 mmol), dimethyl sulfoxide (10 mL), and water (1 mL) to the reaction flask. Purge the mixture three times with nitrogen, and heat to 100 °C with stirring for 1 hour under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was then separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (430 mg, yield: 76%). ESI-MS: 217.0 [M+1] + .

[0425] Preparation of intermediate C10: 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0426]

[0427] Step 1: Synthesis of 2-bromo-6-fluoro-N-(2-methylallyl)pyridine-3-amine

[0428]

[0429] Potassium tert-butoxide (12 mL, 12.0 mmol, 1 M / mL) was added to a tetrahydrofuran (50 mL) solution of 2-bromo-6-fluoropyridin-3-amine (1.91 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (1.48 g, 11.0 mmol) was slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water and ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-10%] to give 2-bromo-6-fluoro-N-(2-methylallyl)pyridin-3-amine (1.7 g, yield: 69%). ESI-MS: 244.8 [M+1] + .

[0430] Step 2: Synthesis of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0431]

[0432] 2-Bromo-6-fluoro-N-(2-methylallyl)pyridine-3-amine (1.55 g, 6.3 mmol), sodium formate (0.52 g, 7.6 mmol), tetrabutylammonium chloride (2.11 g, 7.6 mmol), triethylamine (1.92 g, 19.0 mmol), palladium acetate (0.14 g, 0.6 mmol), and dioxane (80 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, heated to 100 °C and stirred for 5 hours under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-15%] to give 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.54 g, yield: 51%). ESI-MS: 167.0 [M+1] + .

[0433] Preparation of intermediate C11: 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadien[b]pyrrolo[2,3-e]pyridine

[0434]

[0435] Step 1: Synthesis of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one

[0436]

[0437] Nitric acid (65% mmol, 5.4 g, 55.6 mmol) was slowly added dropwise to a concentrated sulfuric acid solution (98% wt, 30 mL) of 450 mg (2.5 mmol) of 1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one at 0 °C. The mixture was stirred at 0 °C for 1 hour, then slowly poured into ice water and stirred for 1 hour. The mixture was filtered, and the filter cake was dried to give 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one (3.5 g, yield: 52.5%). ESI-MS: 181.0 [M+1] + .

[0438] Step 2: Synthesis of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadien[b]pyridine

[0439]

[0440] To a solution of 2.5 g (13.9 mmol) of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one in acetonitrile (50 mL), phosphorus oxychloride (6.4 g, 41.6 mmol) and triethylbenzylammonium chloride (1.9 g, 7.0 mmol) were added. The mixture was stirred at 80 °C for 1 hour, concentrated under reduced pressure to remove the solvent, and the residue was slowly poured into ice water and stirred for 30 minutes. Extraction was performed with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridinium (985 mg, yield: 36.0%). ESI-MS: 198.9 [M+1] + .

[0441] Step 3: Synthesis of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)malonate

[0442]

[0443] Sodium hydride (220 mg, 5.5 mmol) was added to a solution of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine (814 mg, 5.1 mmol) in 10 mL of dimethyl sulfoxide at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Diethyl malonate (840 mg, 4.2 mmol) was added to the mixture, and the reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was then distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine-2-yl)malonate (409 mg, yield: 30.0%). ESI-MS: 323.0 [M+1] + .

[0444] Step 4: Synthesis of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)acetate

[0445]

[0446] To a solution of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)malonate (409 mg, 1.3 mmol) in dimethyl sulfoxide (5 mL), water (0.91 mL, 5.1 mmol) and lithium chloride (267 mg, 6.4 mmol) were added. The mixture was stirred at 100 °C for 24 h. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, the organic layer dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)acetate (240 mg, yield: 76.0%). ESI-MS: 251.0 [M+1] + .

[0447] Step 5: Synthesis of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate

[0448]

[0449] Iodimethane (300 mg, 2.1 mmol) and 18-crown ether-6 (26 mg, 0.1 mmol) were added to a solution of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl) acetate (240 mg, 0.96 mmol) in N,N-dimethylformamide (5 mL) at 0 °C. Sodium hydride (88 mg, 2.2 mmol) was then slowly added. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was then distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate (150 mg, yield: 56.0%). ESI-MS: 279.0 [M+1] + .

[0450] Step 6: Synthesis of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one

[0451]

[0452] Ammonium formate (272 mg, 4.3 mmol) and 10% palladium on carbon (50 mg) were added to a solution of 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate (150 mg, 0.54 mmol) in ethanol (5 mL). The mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressure to give crude 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one, which was used directly in the next step of the reaction. ESI-MS: 203.0 [M+1] + .

[0453] Step 7: Synthesis of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadien[b]pyrrolo[2,3-e]pyridine

[0454]

[0455] Crude 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadien[b]pyrrolo[2,3-e]pyridine-2(1H)-one was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (2 mL, 2.5 M) was added dropwise. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give crude 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadien[b]pyrrolo[2,3-e]pyridine. ESI-MS: 189.0 [M+1] + .

[0456] Preparation of intermediate C12: 5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0457]

[0458] Step 1: Synthesis of 1-(tert-butyl)3-ethyl-2-(6-methyl-3-nitropyridin-2-yl)malonate

[0459]

[0460] 1-tert-butyl-3-ethylmalonate (35.45 g, 188.3 mmol) was slowly added dropwise to a suspension of sodium hydride (6.95 g, 173.8 mmol) in tetrahydrofuran (200 mL) at 0 °C. The mixture was stirred in an ice bath for 0.5 h, and then 2-chloro-6-methyl-3-nitropyridine (25 g, 144.8 mmol) was added to the mixture. The reaction mixture was stirred at 60 °C for 18 h. After the reaction was complete, it was cooled to 0 °C, and the reaction was quenched by slowly adding ice water. The mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 1-(tert-butyl)-3-ethyl-2-(6-methyl-3-nitropyridine-2-yl)malonate (41 g, yield: 73.3%). ESI-MS: 325.0 [M+1] + .

[0461] Step 2: Synthesis of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetic acid ester

[0462]

[0463] Trifluoroacetic acid (100 mL) was added to 1-(tert-butyl)-3-ethyl-2-(6-methyl-3-nitropyridin-2-yl)malonate (41 g, 106.2 mmol), and the mixture was stirred at 60 °C for 2 hours. The reaction solution was distilled under reduced pressure, and the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-15%] to give ethyl-2-(6-methyl-3-nitropyridin-2-yl)acetate (22 g, yield: 89%). ESI-MS: 225.0 [M+1] + .

[0464] Step 3: Synthesis of ethyl 2-(3-amino-6-methylpyridin-2-yl)acetic acid ester

[0465]

[0466] To a methanol (150 mL) solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (22 g, 95.4 mmol), 10% palladium on carbon (3.0 g) was added. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered and distilled under reduced pressure to give ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate (17.5 g, yield: 82%). ESI-MS: 195.0 [M+1] + .

[0467] Step 4: Synthesis of 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0468]

[0469] Ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate (17.5 g, 78.4 mmol) was added to a solution of hydrochloric acid (1 M, 100 mL), and the mixture was stirred at 55 °C for 5 hours. After the reaction was complete, the solution was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was extracted multiple times with dichloromethane:methanol = 10:1. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: dichloromethane / methanol: 0-10%] to give 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (7.8 g, yield: 67%). ESI-MS: 149.0 [M+1] + .

[0470] Step 5: Synthesis of 5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0471]

[0472] Sodium hydride (674.9 mg, 16.8 mmol) was dissolved in N,N-dimethylformamide (20 mL) and hexamethylphosphoric triamine (2 mL), and cooled to 0 °C. A solution of 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.0 g, 6.7 mmol) and 1,3-diiodopropane (0.78 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-30%] to give 5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (260 mg, yield: 20%). ESI-MS: 189.0 [M+1] + .

[0473] Step 6: Synthesis of 5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0474]

[0475] 5'-Methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (263 mg, 1.4 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (1.7 mL, 2.5 M) was added dropwise. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (260 mg, yield: 76%). ESI-MS: 175.0 [M+1] + .

[0476] Preparation of intermediate C13: 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2,2-d2

[0477]

[0478] Step 1: Synthesis of ethyl 2-methyl-2-(6-methyl-3-nitropyridin-2-yl)propionate

[0479]

[0480] Iodimethane (43.68 g, 307.7 mmol) and 18-crown ether-6 (0.39 g, 1.47 mmol) were added to a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl) acetate (23 g, 102.58 mmol) in N,N-dimethylformamide (250 mL) at 0 °C. Sodium hydride (10.3 g, 256.4 mmol) was then slowly added. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was then distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give ethyl 2-methyl-2-(6-methyl-3-nitropyridin-2-yl)propionate (13 g, yield: 49.2%). ESI-MS: 253.0 [M+1] + .

[0481] Step 2: Synthesis of 3,3,5-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0482]

[0483] To a solution of ethyl 2-methyl-2-(6-methyl-3-nitropyridin-2-yl)propionate (5.9 g, 23.4 mmol) in ethanol (100 mL), 10% palladium on carbon (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved in acetic acid (50 mL) and reacted overnight at 90 °C. After the reaction was complete, the solution was distilled under reduced pressure to give 3,3,5-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4.0 g, yield: 97%), which was used directly in the next step. ESI-MS: 163.0 [M+1] + .

[0484] Step 3: Synthesis of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2,2-d2

[0485]

[0486] 3,3,5-Trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (0.6 g, 3.4 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to 0 °C. Deuterated lithium aluminum hydride (0.43 g, 10.2 mmol) was added to the solution. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain a crude product. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-2,2-d2 (0.49 g, yield: 87%). ESI-MS: 165.0 [M+1] + .

[0487] Preparation of intermediate C14: 5-methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0488]

[0489] Step 1: Synthesis of ethyl 2-(methyl-d3)-2-(6-methyl-3-nitropyridin-2-yl)propionate-3,3,3-d3

[0490]

[0491] Deuterated iodomethane (19.16 mL, 307.73 mmol) and 18-crown ether-6 (0.47 g, 1.78 mmol) were added to a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl) acetate (4 g, 17.84 mmol) in N,N-dimethylformamide (30 mL) at 0 °C. The mixture was then slowly added to the solution. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to give ethyl 2-(methyl-d3)-2-(6-methyl-3-nitropyridin-2-yl)propionate-3,3,3-d3 (3.2 g, yield: 91%). ESI-MS: 259.0 [M+1] + .

[0492] Step 2: Synthesis of 5-methyl-3,3-di(methyl-d3)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0493]

[0494] Ammonium formate (3.4 g, 53.7 mmol) and 10% palladium on carbon (300 mg) were added to a solution of ethyl 2-(methyl-d3)-2-(6-methyl-3-nitropyridin-2-yl)propionate-3,3,3-d3 (1.2 g, 4.64 mmol) in ethanol (20 mL). The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressure to give 5-methyl-3,3-di(methyl-d3)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (0.75 g, yield: 88.6%), which was used directly in the next step. ESI-MS: 183.0 [M+1] + .

[0495] Step 3: 5-Methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0496]

[0497] 750 mg (4.12 mmol) of 5-methyl-3,3-di(methyl-d3)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (2 mL, 2.5 M) was added dropwise. The mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 692 mg (89.9%) of 5-methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. ESI-MS: 169.0 [M+1] + .

[0498] Preparation of intermediate C15: 5'-methyl-1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)

[0499]

[0500] Step 1: Synthesis of ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester

[0501]

[0502] Ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (4.9 g, 21.8 mmol) was dissolved in dimethyl sulfoxide (30 mL), followed by the addition of diphenyl(vinyl)sulfonium trifluoromethanesulfonate (7.92 g, 21.8 mmol). The mixture was stirred at room temperature for 10 minutes, and then 2,3,4,6,7,8,9,10-octahydropyrimidine[1,2-a]azapyridine was added. (9.8 mL, 65.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was separated into layers with ethyl acetate (100 mL) and saturated brine (100 mL). The organic phase was concentrated, and the residue was separated by rapid silica gel column chromatography [petroleum ether / ethyl acetate = 3 / 1] to give ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester (5.2 g, 95%). ESI-MS: 251.0 [M+1] + .

[0503] Step 2: Synthesis of 5'-methylspiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0504]

[0505] Ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylic acid ester (5.2 g, 20.8 mmol) was dissolved in ethanol (100 mL), and palladium / carbon (500 mg) was added. The reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Then, concentrated hydrochloric acid (1 mL) was added, and the mixture was heated and stirred for 18 hours until the reaction was complete. The reaction mixture was concentrated by filtration through diatomaceous earth. The residue was separated into layers by ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was separated by rapid silica gel column chromatography [petroleum ether / ethyl acetate = 1 / 1] to give 5'-methylspiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (3.5 g, 96%). ESI-MS: 175.0 [M+1] + .

[0506] Step 3: Synthesis of 5'-methyl-1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)

[0507]

[0508] 5'-Methylspiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (3.0 g, 17.2 mmol) was dissolved in tetrahydrofuran (100 mL). A solution of lithium aluminum hydride in tetrahydrofuran (17.0 mL, 42.5 mmol) was added to the reaction mixture. The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection until the reaction was complete. The reaction mixture was slowly quenched with sodium sulfate decahydrate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [petroleum ether / ethyl acetate = 3 / 1] to give 5'-methyl-1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) (1.0 g, 36%). ESI-MS: 161.0 [M+1] + .

[0509] Preparation of intermediate C16: 3,3-difluoro-5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0510]

[0511] Step 1: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide

[0512]

[0513] 2-Bromo-6-methylpyridin-3-amine (5.0 g, 26.73 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (4.37 g, 32.08 mmol), and 1-methylimidazolium (6.58 g, 80.2 mmol) were dissolved in acetonitrile (150 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (9.00 g, 32.08 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-30%] to give N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide (7.8 g, yield: 95%). ESI-MS: 304.8 [M+1] + .

[0514] Step 2: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide

[0515]

[0516] To a solution of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide (3.0 g, 9.8 mmol) in acetonitrile (50 mL), 1-(chloromethyl)-4-methoxybenzene (2.01 mL, 14.75 mmol) and potassium carbonate (4.08 g, 29.5 mmol) were added. The mixture was stirred at 90 °C for 18 hours. After the reaction was complete, the mixture was filtered and distilled under reduced pressure. The crude product was separated by rapid silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-25%] to give N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide (3.8 g, yield: 90%). ESI-MS: 425.0 [M+1] + .

[0517] Step 3: Synthesis of 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0518]

[0519] To a solution of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide (3.2 g, 7.5 mmol) in dioxane (50 mL), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ide](3-chloropyridine)palladium dichloride (512 mg, 0.7 mmol) and sodium tert-butoxide (1.45 g, 15.0 mmol) were added. The mixture was stirred at 100 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the crude product was distilled under reduced pressure. The crude product was then separated by rapid silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-30%] to give 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (2.0 g, yield: 77%). ESI-MS: 345.0 [M+1] + .

[0520] Step 4: Synthesis of 3,3-difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one

[0521]

[0522] 1.8 g (5.2 mmol) of 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one was dissolved in dichloromethane (3 mL), and trifluoromethanesulfonic acid (3.5 mL) was added to the solution. The mixture was stirred overnight at room temperature. After the reaction was complete, the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the crude product was separated by rapid silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 1.1 g (yield: 93%) of 3,3-difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one. ESI-MS: 225.0 [M+1] + .

[0523] Step 5: Synthesis of 3,3-difluoro-5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)

[0524]

[0525] 250 mg (1.1 mmol) of 3,3-difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium aluminum hydride (1.3 mL, 2.5 M) was added dropwise. The mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 250 mg (100% yield) of 3,3-difluoro-5'-methyl-1,2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine). ESI-MS: 211.0 [M+1] + .

[0526] Preparation of intermediate C17: 5,6-difluoro-3,3-dimethyldihydroindole

[0527]

[0528] Step 1: Synthesis of 5,6-difluoro-3,3-dimethyldihydroindole-2-one

[0529]

[0530] At -78 °C, a 2.5 M solution of n-butyllithium (59.2 mL, 148 mmol) was slowly added dropwise to a suspension of 5,6-difluorodihydroindole-2-one (5.0 g, 29.5 mmol) and lithium chloride (6.2 g, 148 mmol) in tetrahydrofuran (100 mL). The reaction was stirred at -78 °C for 30 min, followed by the addition of iodomethane (21.0 g, 148 mmol). The reaction was continued at -78 °C for 30 min, then stirred at room temperature for 2 h. The phases were separated by ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [petroleum ether / ethyl acetate = 5:1] to give 5,6-difluoro-3,3-dimethyldihydroindole-2-one (3.6 g, yield: 61%). ESI-MS: 198.0 [M+1] + .

[0531] Step 2: Synthesis of 5,6-difluoro-3,3-dimethyldihydroindole

[0532]

[0533] A solution of 3.6 g (18 mmol) of 5,6-difluoro-3,3-dimethyldihydroindole-2-one in tetrahydrofuran (80 mL) was added to a 2.5 M solution of lithium aluminum tetrahydrofuran (28.8 mL, 72 mmol). The mixture was stirred at 50 °C for 3 hours. The solution was quenched with sodium sulfate decahydrate and filtered. The organic phase was concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 3:1] to give 5,6-difluoro-3,3-dimethyldihydroindole (1.8 g, yield: 54%). ESI-MS: 184.0 [M+1] + .

[0534] 1 H NMR (DMSO-d6) δ7.03 (dd, J = 10.4, 8.3 Hz, 1H), 6.40 (dd, J = 11.8, 6.7 Hz, 1H), 5.58 (s, 1H), 3.19 (s, 2H), 1.20 (s, 6H).

[0535] Preparation of intermediate D1: Isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0536]

[0537] At room temperature, isopropyl 2,4-dichloropyrimidine-5-carboxylic acid ester (147.8 mg, 0.63 mmol) was dissolved in isopropanol (5 mL), followed by the sequential addition of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (85.0 mg, 0.52 mmol) and N,N-diisopropylethylamine (101.6 mg, 0.77 mmol). The reaction mixture was stirred in a microwave at 100 °C for 16 hours. After the reaction was complete, the solvent was removed, and the product was separated by silica gel column chromatography [petroleum ether: ethyl acetate = 4:1] to give isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (100 mg, yield: 49.2%). ESI-MS: 361.0 [M+1] + .

[0538] Intermediates D2 to D19 were prepared using the same method as intermediate D1.

[0539]

[0540]

[0541]

[0542]

[0543] Preparation of intermediate E1: Isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0544]

[0545] Isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (100 mg, 0.26 mmol), N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 11,4-methyl-2-nitrobenzene-1,4-diamine (70 mg, 0.26 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (51 mg, 0.08 mmol), palladium acetate (9.3 mg, 0.04 mmol), and cesium carbonate (135.3 mg, 0.4 mmol) were dissolved in dioxane (25 mL). The reaction solution was stirred at 120 °C for 2 hours under nitrogen protection until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 2-((4-(((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (72 mg, yield: 43%). ESI-MS: 593.4 [M+1] + .

[0546] Intermediates E2 to E20 were prepared using the same method as intermediate E1.

[0547]

[0548]

[0549]

[0550]

[0551] Preparation of intermediate E21-1: Preparation of isopropyl 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0552]

[0553] To a solution of 1,4-dioxane (20 mL) of 4-fluoro-2-methoxy-5-nitroaniline (103 mg, 0.55 mmol), isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (200 mg, 0.55 mmol) and p-toluenesulfonic acid monohydrate (95.4 mg, 0.55 mmol) were added. The reaction was stirred at 120 °C for 5 hours. The layers were separated by dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to give isopropyl 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (212 mg, yield: 73.4%). ESI-MS: 511.2 [M+1] + .

[0554] Intermediates E23-1 to E37-1 were prepared using the same method as intermediate E21-1.

[0555]

[0556]

[0557]

[0558] Preparation of intermediate E21: Isopropyl(R)-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0559]

[0560] To a solution of isopropyl 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (100 mg, 0.20 mmol) in 1,4-dioxane (30 mL), (R)-N,N-dimethylpyrrolidine-3-amine (33.6 mg, 0.29 mmol) and diisopropylethylamine (50.6 mg, 0.40 mmol) were added. The reaction was stirred at 120 °C for 18 hours. The layers were separated by dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [dichloromethane:methanol = 10:1] to give isopropyl(R)-2-((4-(3-(dimethylamino)pyrrolidine-1-yl)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (120 mg, yield: 95%). ESI-MS: 605.3 [M+1] + .

[0561] Intermediates E22 to E77 were prepared using the same method as intermediate E21.

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571] Preparation of intermediate E78: Preparation of isopropyl 4-(3,3-dimethyl-5-(prop-1-yn-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0572]

[0573] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (300 mg, 0.45 mmol), propyne (9 mL, 1 M, 9 mmol), tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol), and CuI (17 mg, 0.09 mmol) were dissolved in 10 mL of a mixture of triethylamine and tetrahydrofuran (5:1). The reaction solution was stirred at room temperature under nitrogen protection for 18 hours until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 4-(3,3-dimethyl-5-(prop-1-yn-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (220 mg, yield: 79.5%). ESI-MS: 617.3 [M+1] + .

[0574] Intermediates E79 to E88 were prepared using the same method as intermediate E78.

[0575]

[0576]

[0577] Preparation of intermediate E89: Isopropyl 4-(3,3-dimethyl-5-vinyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0578]

[0579] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (100 mg, 0.15 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxoboropentan (46.8 mg, 0.3 mmol), sodium carbonate (48 mg, 0.45 mmol), palladium acetate (4 mg, 0.02 mmol), and triphenylphosphine (8 mg, 0.3 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL) and water (1 mL). The reaction solution was stirred at 90 °C for 18 hours under nitrogen protection until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 4-(3,3-dimethyl-5-vinyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (66 mg, yield: 73.3%). ESI-MS: 605.3 [M+1] + .

[0580] Intermediate E90 was prepared using the same method as intermediate E89.

[0581]

[0582] Preparation of intermediate E91: Preparation of isopropyl 4-(5-cyano-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0583]

[0584] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (100 mg, 0.15 mmol), zinc cyanide (35.7 mg, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (17.6 mg, 0.015 mmol) were dissolved in N,N-dimethylformamide (10 mL) and water (1 mL). The reaction solution was stirred at 90 °C for 2 hours under nitrogen protection until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 4-(5-cyano-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (82 mg, yield: 89.3%). ESI-MS: 604.2 [M+1] + .

[0585] Intermediate E92: Isopropyl 4-(5-(acetidin-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0586]

[0587] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (100 mg, 0.15 mmol), cyclobutane (100 mg, 1.7 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (37.8 mg, 0.06 mmol), palladium acetate (6.8 mg, 0.03 mmol), and cesium carbonate (99 mg, 0.3 mmol) were dissolved in dioxane (12 mL). The reaction solution was stirred at 120 °C for 2 hours under nitrogen protection until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 4-(5-(acadidin-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (52 mg, yield: 53.9%). ESI-MS: 634.5 [M+1] + .

[0588] Preparation of intermediate E93-1: Preparation of isopropyl 2-((4-(((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0589]

[0590] To a solution of isopropyl 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (400 mg, 0.78 mmol) in 1,4-dioxane (30 mL), 2-(methylamino)ethane-1-ol (0.10 mL, 1.18 mmol) and diisopropylethylamine (0.26 mL, 1.57 mmol) were added. The reaction was stirred at 120 °C for 18 hours. The layers were separated by dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 2-((4-(((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (120 mg, yield: 95%). ESI-MS: 566.3 [M+1] + .

[0591] Intermediates E95-1 to E97-1 and E99-1 were prepared using the same method as intermediate E93-1.

[0592]

[0593]

[0594] Preparation of intermediate E93-2: Preparation of isopropyl 2-((2-methoxy-4-(methyl(2-(((methanesulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0595]

[0596] A solution of isopropyl 2-((4-(((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (410 mg, 0.73 mmol) in dichloromethane (10 mL) was cooled to 0 °C, and N,N-diisopropylethylamine (0.36 mL, 2.18 mmol) and methanesulfonyl chloride (0.07 mL, 0.87 mmol) were added. The reaction mixture was stirred at 0 °C for 0.5 hours. After solvent removal, silica gel column chromatography [dichloromethane:methanol = 10:1] yielded isopropyl 2-((2-methoxy-4-(methyl(2-(((methanesulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (470 mg, yield: 89%). ESI-MS: 644.3 [M+1] + .

[0597] Intermediates E95-2 to E97-2 and E99-2 were prepared using the same method as intermediate E93-2.

[0598]

[0599]

[0600] Intermediate E93: Isopropyl 2-((2-methoxy-4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0601]

[0602] In a solution of isopropyl 2-((2-methoxy-4-(methyl(2-(((methanesulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (1.0 g, 4.5 mmol) in acetonitrile (30 mL), pyrrolidine (0.03 mL, 0.37 mmol) and potassium carbonate (1.2 g, 9.0 mmol) were added. The reaction mixture was stirred at 50 °C for 18 hours. After solvent removal, silica gel column chromatography [dichloromethane:methanol = 10:1] yielded isopropyl 2-((2-methoxy-4-(methyl(2-(pyrrolidine-1-yl)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (40 mg, yield: 31.7%). ESI-MS: 310.3 [M / 2+1] + .

[0603] Intermediates E94 to E100 were prepared using the same method as intermediate E93.

[0604]

[0605] Preparation of intermediate F1: Isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0606]

[0607] A 10% palladium on carbon (10 mg) was added to a 20 mL methanol solution of isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (72 mg, 0.11 mmol). The reaction was stirred at room temperature for 0.5 h, filtered, and concentrated to give isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (65 mg, yield: 86.3%). ESI-MS: 563.3 [M+1] + .

[0608] Preparation of intermediate F2: Isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-isopropoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0609]

[0610] Iron powder (104 mg, 1.87 mmol) and ammonium chloride (101 mg, 1.87 mmol) were added to a methanol / water mixture [methanol:water (v / v) = 2:1] (30 mL) of isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-isopropoxy-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (129 mg, 0.21 mmol) . The reaction mixture was stirred at 100 °C for 1 hour and then filtered. The resulting solution was separated into layers with ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated to give isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-isopropoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (92 mg, yield: 74.6%). ESI-MS: 591.4 [M+1] + .

[0611] Intermediates F3 to F93 were prepared using the same methods as intermediates F1 or F2.

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626] Preparation of intermediate G1: Preparation of isopropyl 2-((5-acryloylamino-4-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0627]

[0628] Isopropyl 2-((5-amino-4-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (120 mg, 0.19 mmol) was dissolved in anhydrous acetonitrile / water (3 mL / 1 mL). N,N-diisopropylethylamine (71.7 mg, 0.56 mmol) was added to the solution. Acryloyl chloride (33.5 mg, 0.37 mmol) was added to the reaction solution at 0 °C. After stirring for 30 minutes, the mixture was separated into layers with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography [40-50% acetonitrile / water] to give isopropyl 2-((5-acryloylamino-4-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (110 mg, yield: 64.3%). ESI-MS: 703.4 [M+1] + .

[0629] Intermediates G2 to G5 were prepared using the same method as intermediate G1.

[0630]

[0631] II. Preparation of Specific Embodiments

[0632] Example 1: Preparation of isopropyl 2-((5-acryloylamino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0633]

[0634] Isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (65 mg, 0.1 mmol, 1 eq.) was dissolved in acetonitrile / water (3 mL / 1 mL). N,N-diisopropylethylamine (20 mg, 0.15 mmol, 1.5 eq.) was added to the solution. Acryloyl chloride (12 mg, 0.13 mmol, 1.3 eq.) was added to the reaction solution at 0 °C. The reaction solution was stirred at 0 °C for 10 minutes. Concentrated and separated by reversed-phase column chromatography [40-50% acetonitrile / water], the product yielded isopropyl 2-((5-acryloylamino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (7.2 mg, yield: 11.2%). ESI-MS: 617.4 [M+1] + .

[0635] 1 HNMR(MeOH-d4)δ8.97(s,1H),8.55(s,1H),7.11(d,J=8.2Hz,1H),6.92–6.79(m ,2H),6.53–6.39(m,1H),6.26(dd,J=17.0,1.9Hz,1H),5.70(dd,J=10.1,1.9Hz ,1H),4.98–4.81(m,1H),3.94(s,2H),3.83(s,3H),2.95(t,J=6.0Hz,2H),2.59 (s, 3H), 2.37 (d, J = 6.0Hz, 5H), 2.20 (s, 6H), 1.31 (s, 6H), 1.05 (d, J = 6.2Hz, 6H).

[0636] The following examples were prepared according to the preparation method of Example 1. Examples 60-62 were obtained by chiral resolution. Resolution conditions: chiral column: IC column, column temperature: 40°C, mobile phase: n-hexane (0.1% diethylamine): ethanol (0.1% diethylamine) = 50:50 or 60:40, flow rate: 1 mL per minute.

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650] The NMR data of the compounds prepared in the above examples are as follows:

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664] Example 9: Preparation of isopropyl 2-((5-acryloylamino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(5-ethynyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0665]

[0666] Step 1: Synthesis of ethyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester

[0667]

[0668] 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (800 mg, 3.5 mmol, 1 eq.) and ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ester (819 mg, 3.5 mmol, 1 eq.) were dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (253.66 mg, 10.6 mmol, 3 eq.) was added to the reaction solution at 0 °C. The reaction was stirred at room temperature for 1 hour. The mixture was separated into layers by ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether:ethyl acetate = 4:1] to give ethyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester (660 mg, yield: 44%). ESI-MS: 423.0, 425.0 [M+1] + .

[0669] Step 2: Synthesis of 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid

[0670]

[0671] Ethyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester (660 mg, 1.6 mmol, 1 eq.) and lithium hydroxide (382 mg, 7.8 mmol, 5 eq.) were dissolved in methanol / water / tetrahydrofuran (3 mL / 3 mL / 6 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was adjusted to acidity with 1 N hydrochloric acid solution and extracted with dichloromethane. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid (440 mg, yield: 71%). ESI-MS: 395.1, 397.1 [M+1] + .

[0672] Step 3: Synthesis of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester

[0673]

[0674] To a solution of 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid (440 mg, 1.1 mmol) in dichloromethane (15 mL), N,N-dimethylformamide (0.05 mL, 0.68 mmol) and oxalyl chloride (0.20 mL, 2.28 mmol) were added. After stirring the reaction mixture at room temperature for 1 hour, isopropanol (6 mL) was added, and the mixture was heated to 60 °C and stirred for 1 hour. The organic phase was separated by ethyl acetate and water, washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether:ethyl acetate = 3:1] to give isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester (200 mg, yield: 40%). ESI-MS: 437.0, 439.0 [M+1] + .

[0675] Step 4: Synthesis of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methanesulfonyl)pyrimidine-5-carboxylic acid ester

[0676]

[0677] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylic acid ester (200 mg, 0.46 mmol, 1 eq.) was added to a tetrahydrofuran / water solution (6 mL / 0.6 mL) with potassium persulfate (562 mg, 0.92 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 3 hours. The phases were separated by ethyl acetate and water, and the organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether: ethyl acetate = 5:1] to give isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methanesulfonyl)pyrimidine-5-carboxylic acid ester (42 mg, yield: 20%). ESI-MS: 469.1, 471.1 [M+1] + .

[0678] Step 5: Synthesis of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0679]

[0680] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methanesulfonyl)pyrimidine-5-carboxylic acid ester (42 mg, 0.09 mmol, 1 eq.) and N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carboxamide (32 mg, 0.11 mmol, 1.2 eq.) were dissolved in N,N-dimethylacetamide (5 mL). Sodium hydride (25 mg, 0.61 mmol, 3 eq.) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Water was added, and stirring continued for 0.5 hours. The organic phase was separated by ethyl acetate and water, washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether:ethyl acetate = 4:1] to give isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (46 mg, yield: 78%). ESI-MS: 657.3, 659.3 [M+1] + .

[0681] Step 6: Synthesis of isopropyl 4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester

[0682]

[0683] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (46 mg, 0.07 mmol, 1 eq.), trimethylethynylsilane (21 mg, 0.21 mmol, 3 eq.), triethylamine (21 mg, 0.21 mmol, 3 eq.), bis(triphenylphosphine)palladium dichloride (21 mg, 0.28 mmol, 0.4 eq.), and cuprous iodide (5 mg, 0.28 mmol, 0.4 eq.) were dissolved in tetrahydrofuran (6 mL). The reaction solution was stirred at room temperature under nitrogen protection for 3 hours until the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography [dichloromethane:methanol = 10:1] to give isopropyl 4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (36 mg, yield: 76.21%). ESI-MS: 675.3 [M+1] + .

[0684] Step 7: Synthesis of isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0685]

[0686] Iron powder (30 mg, 0.53 mmol, 10 eq.) and ammonium chloride (29 mg, 0.53 mmol, 10 eq.) were added to a suspension of isopropyl 4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylic acid ester (36 mg, 0.05 mmol, 1 eq.) in ethanol / water (3 mL / 3 mL). The reaction was stirred and refluxed at 95 °C for 2 hours. The mixture was separated into layers with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried with anhydrous sodium sulfate, filtered, and concentrated to give isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (30 mg, yield: 73.17%). ESI-MS: 645.4 [M+1] + .

[0687] Step 8: Synthesis of isopropyl 2-((5-acryloylamino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(5-ethynyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0688]

[0689] Isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (30 mg, 0.05 mmol, 1 eq.) was dissolved in anhydrous acetonitrile / water (3 mL / 3 mL). N,N-diisopropylethylamine (31 mg, 0.25 mmol, 5 eq.) was added to the solution. Acryloyl chloride (9 mg, 0.1 mmol, 2 eq.) was added to the reaction solution at 0 °C. After stirring for 30 minutes, potassium carbonate (35 mg, 0.25 mmol, 5 eq.) and ethanol (3 mL) were added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. The mixture was separated into layers using dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reversed-phase column chromatography [40-50% acetonitrile / water] to give isopropyl 2-((5-acryloylamino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(5-ethynyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (7.6 mg, yield: 24%). ESI-MS: 627.3 [M+1] + .

[0690] 1 HNMR(DMSO-d6)δ10.08(s,1H),8.83–8.57(m,3H),7.19(t,J=14.6Hz,2H),7.01(s,1H) ,6.41(dd,J=16.9,10.1Hz,1H),6.23(dd,J=16.9,2.2Hz,1H),5.75(dd,J=10.1,2.2Hz, 1H),4.93(p,J=6.2Hz,1H),4.16(s,1H),3.93(s,2H),3.81(s,3H),2.88(t,J=5.8Hz,2H ), 2.72 (s, 3H), 2.30 (d, J = 5.8Hz, 2H), 2.20 (s, 6H), 1.28 (s, 6H), 1.12 (d, J = 6.2Hz, 6H).

[0691] Example 15: Preparation of isopropyl 2-((5-acryloylamino-2-methoxy-4-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester

[0692]

[0693] Isopropyl 2-((5-acryloylamino-4-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (110 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the residue was separated by reversed-phase column chromatography to give isopropyl 2-((5-acryloylamino-2-methoxy-4-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylic acid ester (19.1 mg, yield: 19.0%). ESI-MS: 603.4 [M+1] + .

[0694] 1 HNMR(DMSO-d6)δ10.33(s,1H),8.81(s,1H),8.55(d,J=10.6Hz,2H),7.20(s,1H),6.94(s,1H ),6.82(d,J=8.3Hz,1H),6.55(dd,J=16.9,10.1Hz,1H),6.22(dd,J=17.0,2.2Hz,1H),5.72(d d,J=10.1,2.2Hz,1H),4.92(p,J=6.2Hz,1H),3.86(s,2H),3.80(s,3H),2.88–2.81(m,2H),2. 70 (s, 3H), 2.59 (t, J = 5.4Hz, 2H), 2.36 (d, J = 17.4Hz, 6H), 1.26 (s, 6H), 1.12 (d, J = 6.3Hz, 6H).

[0695] The following examples were prepared according to the preparation method of Example 15:

[0696]

[0697]

[0698] The NMR data of the compounds prepared in the above examples are as follows:

[0699]

[0700] Biological testing evaluation

[0701] (Cell proliferation experiment)

[0702] (I) Reagents and Consumables

[0703] Fetal bovine serum FBS (GBICO, Cat#10099-141);

[0704] Chemiluminescence cell viability assay kit (Promega, Cat#G7572);

[0705] Black transparent flat-bottomed 96-hole board Cat#3603).

[0706] (II) Instruments

[0707] SpectraMax Multilabel Microplate Analyzer MD,2104-0010A;

[0708] Carbon dioxide incubator, Thermo Scientific 3100 series;

[0709] Biosafety cabinet, Thermo Scientific, 1300 series A2 model;

[0710] Inverted microscope, Olympus, CKX41SF;

[0711] Siemens refrigerator KK25E76TI.

[0712] (III) Cell lines and culture conditions

[0713]

[0714] (IV) Experimental Procedure

[0715] 1. Cell culture and seeding:

[0716] (1) Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. Cell viability is assessed using the trypan blue exclusion method to ensure that the cell viability is above 90%.

[0717] (2) Adjust the cell concentration to achieve the desired final density; add 90 μL of cell suspension to a 96-well plate.

[0718] (3) Incubate the cells overnight in a 96-well plate at 37°C, 5% CO2 and 95% humidity.

[0719] 2. T0 baseline data:

[0720] (1) Add 10 μL of PBS to each well of a T0 plate containing cells.

[0721] (2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0722] (3) Add an equal volume of CTG solution to each well.

[0723] (4) Vibrate on a fixed-track shaker for 5 minutes to lyse the cells.

[0724] (5) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0725] (6) Read the T0 fluorescence signal value.

[0726] 3. Compound dilution and addition

[0727] (1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10mM stock solution.

[0728] (2) Prepare compound solutions diluted 1000 times and 3.16 times.

[0729] (3) Dilute the 1000× diluted compound solution 100-fold with PBS to prepare 10-fold compound solutions, with a maximum concentration of 10 μM. Nine concentrations were prepared and diluted 3.16-fold. 10 μL of the drug solution was added to each well of a 96-well plate and cells were seeded. Three replicate wells were set up for each compound concentration, and the final concentration of DMSO was 0.1%.

[0730] (4) Place the cells in a 96-well plate containing the drug at 37°C, 5% CO2 and 95% humidity for 72 hours, and then perform CTG analysis.

[0731] 4. Fluorescence signal reading

[0732] (1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0733] (2) Add an equal volume of CTG solution to each well.

[0734] (3) Vibrate on a fixed-track shaker for 5 minutes to lyse the cells.

[0735] (4) Place the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal.

[0736] (5) Read the fluorescence value.

[0737] 5. Data Processing

[0738] Data were analyzed using GraphPad Prism 7.0 software, and a nonlinear S-curve regression was used to fit the data to obtain the dose-response curve, from which the IC was calculated. 50Values ​​(unit: nM), specific experimental results are shown in Table 1:

[0739] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0740] Table 1: Results of Biological Tests

[0741]

[0742]

[0743] Based on the bioactivity data of the compounds in the specific embodiments, the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutations at the cellular level, and the selectivity for EGFR WT reaches more than 10 times, with some compounds even achieving more than 20 times selectivity. Compared with the less than 5 times selectivity of positive compounds, the series of compounds of the present invention have higher selectivity and better development prospects.

[0744] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above disclosure of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Compounds of formula (II), their stereoisomers or pharmaceutically acceptable salts thereof: ， in, Y1 is CH or N; Z is CH or N; R1is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl and 5- to 8-membered heteroaryl, or R1and R 10 together with the moiety to which they are directly attached form a C 4-6 cycloalkyl, which is optionally further substituted by one or more substituents selected from halogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 2a and R 2b Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, or R 2a and R 2b Together with the carbon atom directly attached to it, they form C 3-6 Cycloalkyl groups, wherein the above groups may optionally be further replaced by one or more substituents selected from deuterium and halogens; R 3a and R 3b Each is independently either hydrogen or deuterium; R4 is selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl groups, wherein the above groups may optionally be further replaced by one or more substituents selected from deuterium and halogens; R5 is selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl; R6 is hydrogen or C. 1-4 alkyl; R7 is hydrogen or C. 1-4 alkyl; R8 and R9 are each independently selected from hydrogen and C. 1-4 Alkyl and C 3-6 Cycloalkyl groups, or R8 and R9 together with the nitrogen atom directly attached to them, form 3-6 membered heterocyclic groups, which may optionally be further substituted with one or more deuterium atoms; Alternatively, one of R6, R7, or R9 and R5 together with their directly attached portion form a 4-6 membered heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further selected from one or more halogens and C. 1-4 Substituents of alkyl groups, Alternatively, R7 and R8, together with their directly attached portions, form a 4-6 membered heterocyclic group. or, It has the following structure: R8 is as defined above; R 10 It is hydrogen or halogen; n is 0.

2. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R1 is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, or R1 and R 10 Together with the portion directly attached thereto, a cyclopentyl group is formed, which may be further replaced by one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl. R 10 It is selected from hydrogen, fluorine, chlorine and bromine.

3. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R4 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, and the above groups may optionally be further replaced by one or more substituents selected from deuterium and fluorine.

4. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R 2a and R 2b Each is independently selected from hydrogen, deuterium, methyl, ethyl, and isopropyl, or, R 2a and R 2b Together with the carbon atom directly attached thereto, it forms a cyclopropyl, cyclobutyl, or cyclopentyl group, which may be further replaced by one or more substituents selected from deuterium, fluorine, chlorine, and bromine.

5. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, R5 is selected from hydrogen, methyl, ethyl, isopropyl, trideuteryl, and dideuteryl; R6 is selected from hydrogen, methyl, ethyl, and isopropyl; R7 is selected from hydrogen, methyl, ethyl, and isopropyl; R8 and R9 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, or R8 and R9 together with the nitrogen atom directly attached to them form a 4-6 membered heterocyclic group. Alternatively, one of R6, R7, or R9 and R5 together with their directly attached portion form a 4-6 membered heterocyclic heterocyclic group, wherein the other two of R6, R7, or R9 are as defined above, and the 4-6 membered heterocyclic group is optionally further selected from one or more halogens and C. 1-4 Substituents of alkyl groups, Alternatively, R7 and R8, together with their directly attached portions, form a 4-6 membered heterocyclic group. or, It has the following structure: R8 is defined as previously.

6. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, It has the following structure: ， Each R5 is independently selected from hydrogen, methyl, ethyl, trideuterium methyl and dideuterium methyl; Each R6 is independently selected from hydrogen, methyl, ethyl, and isopropyl; R7 is hydrogen or C. 1-4 alkyl; Each R8 and R9 is independently selected from hydrogen, methyl, ethyl, isopropyl, trideuteryl, dideuteryl, cyclopropyl, and cyclobutyl, or R8 and R9 together with the nitrogen atom directly attached to them form a 4-6 membered heterocyclic group; R a It is hydrogen or halogen; R b It is hydrogen or halogen.

7. The compound of formula (II) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Selected from the following compounds: and .

8. A method for preparing a compound of formula (II) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Among them, Y1, Z, R1, R 2a R 2b R 3a R 3b , R4, R5, R6, R7, R8, R9, R 10 and n as defined in claim 1.

9. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound of formula (II) according to any one of claims 1-7, its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of tumors at least partially associated with EGFR exon 20 insertion mutations D770-N771ins_SVD or V769_D770insASV.

11. The use according to claim 10, characterized in that, The tumor is cancer.

12. Use of the compound of formula (II) according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of pancreatic cancer, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast tumors, gynecological tumors, urological tumors, skin tumors and sarcomas at least partially associated with EGFR exon 20 insertion mutations D770-N771ins_SVD or V769_D770insASV.

13. The use according to claim 12, characterized in that, The breast tumor is breast cancer; the gynecological tumor is ovarian cancer or uterine cancer; the gastrointestinal tumor is gastric cancer or colon cancer; the myelodysplastic syndrome is leukemia; the thoracic tumor is lung cancer; and the head and neck tumor is inverted papilloma of the nasal cavity and sinuses.

14. The use according to claim 13, characterized in that, The lung cancer is non-small cell lung cancer; the inverted papillary tumor of the nasal cavity and sinuses is squamous cell carcinoma of the nasal cavity and sinuses.

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