Pyrimidine or pyridine derivatives, their preparation method and pharmaceutical applications

Abstract

The present invention relates to pyrimidine or pyridine derivatives and their preparation and pharmaceutical application. In particular, the present invention relates to a pyrimidine or pyridine derivative having a structure represented by formula (I), its preparation, a pharmaceutical composition containing it, and its use as an EGFR inhibitor and in the manufacture of a drug for treating and / or preventing cancer, tumor or metastatic disease at least in part associated with an insertion, deletion or other mutation in EGFR exon 20, particularly in the manufacture of a drug for treating and / or preventing hyperproliferative disease and cell death-induced disorder disease. Here, each substituent in formula (I) is as defined in the specification. JPEG2024524262000302.jpg5192

Description

[Technical Field]

[0001] The present invention relates to the field of drug synthesis, specifically to pyrimidine or pyridine derivatives and their preparation methods and pharmaceutical applications. [Background technology]

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

[0003] While conventional EGFR activating mutations (exons 19 and 21) and drug-resistant mutations (T790M) can be inhibited by existing drugs, exon 20 insertion mutations result in constitutive activation of EGFR signaling and are less sensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include insertions or repeats of one to seven amino acids between amino acids 762 and 774 of the EGFR protein. In NSCLC, EGFR exon 20 mutations account for 4–10% of all EGFR mutations. These mutations interact with other known oncogene driver mutations and are more prevalent in women, non-smokers, Asian populations, and adenocarcinomas in non-small cell lung cancer patients. In addition to NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, namely nasal squamous cell carcinoma (SNSCC). Similar exon 20 insertion mutations have also been found in HER2, another member of the EGFR family.

[0004] Retrospective studies have shown that currently available first-, second-, and third-generation EGFR inhibitors have limited therapeutic efficacy against exon 20 insertion mutations, excluding the A763-Y764insFQEA mutation. The irreversible inhibitor poziotinib and the EGFR / MET bispecific antibody amivantamab are currently undergoing clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, have demonstrated clinically significant efficacy in patients with EGFR exon 20 non-small cell lung cancer. However, their limited selectivity over wild-type EGFR may lead to unavoidable adverse reactions and potentially dose-limiting toxicity. Clinical trials have also shown that existing compounds may suffer from insufficient exposure. Therefore, small molecule inhibitors with higher exposure and / or higher selectivity for EGFR exon 20 insertion mutations are desperately needed for these patients. Summary of the Invention

[0005] The present invention aims to provide pyrimidine or pyridine derivatives, their preparation methods, and pharmaceutical applications. The series of compounds of the present invention have strong inhibitory effects on the cytological activity of EGFR exon 20 insertions, deletions, or other mutations, and are highly selective for wild-type EGFR. They are therefore widely applicable to the production of drugs for treating and / or preventing cancers, tumors, or metastatic diseases, at least some of which are associated with EGFR exon 20 insertions, deletions, or other mutations, particularly drugs for treating hyperproliferative diseases and cell death-induced disorders. Therefore, the development of next-generation EGFR inhibitors is desired.

[0006] A first aspect of the present invention provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X is CH or N, Y1 and Y2 are each independently CH or N, and Z is CR 11 or N, R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 Alternatively, R1 and adjacent R 10 C together with the parts directly linked to them 3-12 forming a cycloalkyl group or a 3- to 12-membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10Aryl group, 5-10 membered heteroaryl group, ═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 and optionally substituted with one or more substituents selected from the group consisting of:

[0007] R 2a and R 2b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 and optionally substituted with one or more substituents selected from the group consisting of:

[0008] R 3a and R 3b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups; R4 is hydrogen, deuterium, C 1-10 Alkyl group, C 2-10Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl groups, ═O, cyano groups, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of: R5 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-4 Alkenyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0009] R6 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 selected from the group consisting of R7 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 selected from the group consisting of

[0010] R8 and R9 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-4 Alkenyl group, C 3-6 Alternatively, R8 and R9 together with the nitrogen atom directly connected thereto form a 3- to 12-membered heterocyclic group, which may optionally further contain deuterium, halogen, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0011] Alternatively, one of R6, R7 or R9 and R5 together with the moiety directly linked thereto form a 4-6 membered heterocyclic group, and the other two of R6, R7 or R9 are as defined above, and the 4-6 membered heterocyclic group optionally further contains deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 and optionally substituted with one or more substituents selected from the group consisting of:

[0012] Alternatively, R7 and R8 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 , -C0-8 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 and optionally substituted with one or more substituents selected from the group consisting of:

[0013] or, [ka] has the following structure: [ka] , where R8 is as defined above;

[0014] Each R 10 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-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, two R 10 together with the parts directly connected to them. 3-12 forming a cycloalkyl group or a 3- to 12-membered heterocyclic group,

[0015] R 11 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -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 selected from the group consisting of Each R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5- to 10-membered heteroaryl groups, and -C 0-8 Alkyl-NR 15 R 16 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxy group, oxo, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0016] Each R 13 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl groups, oxo, cyano groups, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0017] Each R 14 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxy group, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0018] Each R 15 and R 16 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkoxy group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 alkanoyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups;

[0019] Alternatively, R 15 and R 16together with the nitrogen atom to which they are directly attached form a 5-10 membered heterocyclic or 5-10 membered heteroaryl group, which may optionally further contain deuterium, halogen, hydroxyl, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; m is 0, 1, or 2; n is 0, 1, or 2, and each r is independently 0, 1, or 2;

[0020] In a preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Z is CR 11 or N, R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 Alternatively, R1 and adjacent R 10 C together with the parts directly linked to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═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(=NR15 )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 and optionally substituted with one or more substituents selected from the group consisting of:

[0021] R 2a and R 2b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═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 , -C0-4 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 and optionally substituted with one or more substituents selected from the group consisting of:

[0022] R 3a and R 3b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups; R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl groups, ═O, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15R 16 and optionally substituted with one or more substituents selected from the group consisting of: R5 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0023] R6 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 selected from the group consisting of R7 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 selected from the group consisting of

[0024] R8 and R9 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Alternatively, R8 and R9 together with the nitrogen atom directly connected thereto form a 3- to 6-membered heterocyclic group, which may optionally further contain deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0025] Alternatively, one of R6, R7 or R9 and R5 together with the moiety directly linked thereto form a 4-6 membered heterocyclic group, and the other two of R6, R7 or R9 are as defined above, and the 4-6 membered heterocyclic group optionally further contains deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═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(=NR15 )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 and optionally substituted with one or more substituents selected from the group consisting of:

[0026] Alternatively, R7 and R8 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═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 15R 16 and -C 0-4 Alkyl-N(R 15 )-C(O)R 14 and optionally substituted with one or more substituents selected from the group consisting of:

[0027] or, [ka] has the following structure: [ka] , where R8 is as defined above;

[0028] Each R 10 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 when m=2, two R 10 C together with the parts directly linked to them 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclic group,

[0029] R 11 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -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 14and where R 12 , R 13 , R 14 , R 15 , R 16 , m, n and r are as described for compounds of formula (I).

[0030] In a preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups and -C 0-4 Alkyl-NR 15 R 16 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxy group, oxo, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0031] Each R 13 are independently hydrogen, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl groups, oxo, cyano groups, C 1-4 Alkyl group, C 1-4Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of: Each R 14 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxy group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0032] Each R 15 and R 16 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkoxy group, C 1-4Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 alkanoyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups;

[0033] Alternatively, R 15 and R 16 together with the nitrogen atom to which they are directly attached form a 5-8 membered heterocyclic or 5-8 membered heteroaryl group, which may optionally further contain deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkanoyl groups.

[0034] In a preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the compound represented by formula (I) is a compound represented by the following formula (II): [ka] (In the formula, Y1 is CH or N, Z is CH or N, R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -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 Alternatively, R and R 10C together with the parts directly linked to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =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 and optionally substituted with one or more substituents selected from the group consisting of:

[0035] R 2a and R 2b are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups, or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =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 and optionally substituted with one or more substituents selected from the group consisting of:

[0036] R 3a and R 3b are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 and a cycloalkyl group and a 3- to 6-membered heterocyclic group, said group optionally further comprising deuterium, halogen, hydroxy group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0037] R5 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R6 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -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 selected from the group consisting of R7 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8Aryl groups, 5-8 membered heteroaryl groups, -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 selected from the group consisting of

[0038] R8 and R9 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 or R8 and R9 together with the nitrogen atom directly connected thereto form a 3- to 6-membered heterocyclic group, which may optionally further contain deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -C 0-4 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of: Alternatively, one of R6, R7 or R9 and R5 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, and the other two of R6, R7 or R9 are as defined above, and the 4-6 membered heterocyclic group optionally further contains deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =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 and optionally substituted with one or more substituents selected from the group consisting of:

[0039] Alternatively, R7 and R8 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =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 and optionally substituted with one or more substituents selected from the group consisting of:

[0040] or, [ka] has the following structure: [ka] , where R8 is as defined above; R 10 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -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 16and -N(R 15 )-C(O)R 14 selected from the group consisting of where R 12 , R 13 , R 14 , R 15 , R 16 , n and r are as defined for compounds of formula (I).

[0041] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R1 is hydrogen, deuterium, halogen, a cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -OR 13 , -OC(O)R 14 and -NR 15 R 16 Alternatively, R and R 10 C together with the parts directly linked to them 4-6 forming a cycloalkyl group or a 4-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =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(=NR16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 and optionally substituted with one or more substituents selected from the group consisting of:

[0042] R 2a and R 2b are independently hydrogen, deuterium, and C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups; R 3a and R 3b are independently hydrogen, deuterium, halogen, C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R4 is hydrogen, deuterium, C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, ═O, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0043] R5 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R6 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R7 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R8 and R9 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl groups and C 3-6 Alternatively, R8 and R9 together with the nitrogen atom to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups and -NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of:

[0044] Alternatively, one of R6, R7 or R9 and R5 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, and the other two of R6, R7 or R9 are as defined above, and the 4-6 membered heterocyclic group optionally further contains deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl groups and C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups;

[0045] Alternatively, R7 and R8 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl groups and C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups;

[0046] or, [ka] has the following structure: [ka] , where R8 is as defined above; R 10 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl groups and C 3-6 cycloalkyl groups, where R 12 , R 13 , R 14 , R 15 , R 16 , n and r are as described for the compound of formula (II).

[0047] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R1 is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group, a methyl group, an ethyl group, an isopropyl group, a vinyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a triazolyl group, a methoxy group, an amino group, a dimethylamino group, and a methylamino group, or R1 and R 10 together with the moiety to which they are directly linked form a cyclopentyl group, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R 10 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl.

[0048] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R4 is selected from the group consisting of hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, and a cyclobutyl group, and the group may optionally further contain deuterium, fluorine, C 1-4 Alkyl groups and C 3-6 It may be substituted with one or more substituents selected from the group consisting of cycloalkyl groups.

[0049] In a more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R 2a and R 2b are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl; or R 2a and R 2b together with the carbon atom directly linked thereto form a cyclopropyl, cyclobutyl, or cyclopentyl group, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl.

[0050] In a more preferred embodiment, the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 3a and R 3b are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl.

[0051] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R5 is selected from the group consisting of hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a difluoromethyl group, a trideuteromethyl group, a diduteromethyl group, a cyclopropyl group, and a cyclobutyl group; R6 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R7 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R8 and R9 are each independently selected from the group consisting of hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a difluoromethyl group, a trideuteromethyl group, a diduteromethyl group, a cyclopropyl group, and a cyclobutyl group, or R8 and R9 together with the nitrogen atom directly linked thereto form a 4- to 6-membered heterocyclic group;

[0052] Alternatively, one of R6, R7 or R9 and R5 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, and the other two of R6, R7 or R9 are as defined above, and the 4-6 membered heterocyclic group optionally further contains deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl groups and C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups; Alternatively, R7 and R8 together with the moiety to which they are directly linked form a 4-6 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl groups and C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups;

[0053] or, [ka] has the following structure: [ka] , where R8 is as defined above.

[0054] In a further more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] has the following structure: [ka] and wherein each R5 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, trideuteromethyl, and dideuteromethyl; each R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R7 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, each R8 and R9 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; or R8 and R9 together with the nitrogen atom directly linked thereto form a 4- to 6-membered heterocyclic group; R a is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6cycloalkyl groups, R b is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 The group consisting of cycloalkyl groups is selected from the group consisting of:

[0055] In the most preferred embodiment, the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds: [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] A second aspect of the present invention provides a process for producing a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps: [ka] (where 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 for compounds of formula (I).

[0066] A third aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0067] The present invention further relates to the use of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing cancer, tumor, or metastatic disease, at least in part, associated with insertion, deletion, or other mutation in EGFR exon 20.

[0068] The present invention further relates to the use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders.

[0069] The present invention further relates to the use of the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating 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 tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal cavity and paranasal sinus inverted papilloma, or nasal cavity and paranasal sinus squamous cell carcinoma associated with nasal cavity and paranasal sinus inverted papilloma, at least some of which are associated with insertions, deletions, or other mutations in EGFR exon 20.

[0070] The present invention further relates to a compound represented by the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use as a drug.

[0071] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer, tumor, or metastatic disease, at least some of which are associated with insertion, deletion, or other mutation in EGFR exon 20.

[0072] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in preventing and / or treating tumors, cancers, and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders.

[0073] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating and / or preventing 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 tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal cavity and paranasal sinus inverted papilloma, or nasal cavity and paranasal sinus squamous cell carcinoma associated with nasal cavity and paranasal sinus inverted papilloma, at least some of which are associated with insertions, deletions, or other mutations in EGFR exon 20.

[0074] The present invention further relates to a method for treating and / or preventing cancer, tumor or metastatic disease associated, at least in part, with insertions, deletions or other mutations in EGFR exon 20, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0075] The present invention further relates to a method for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0076] The present invention further relates to a method for treating and / or preventing 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 tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma, at least some of which are associated with insertions, deletions or other mutations in EGFR exon 20, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0077] Specific Embodiments As a result of extensive and in-depth research, the inventors of the present application have for the first time developed pyrimidine or pyridine derivatives having the structure represented by the following formula (I). The series of compounds of the present invention are widely applicable to the manufacture of drugs for treating and / or preventing cancer, tumor, or metastatic diseases, at least some of which are associated with insertion, deletion, or other mutations in EGFR exon 20, particularly for treating hyperproliferative diseases and cell death-induced disorders, and therefore the development of next-generation EGFR inhibitors is desired. Based on this, the present invention has been completed.

[0078] Special Note: Unless stated or otherwise specified to the contrary, the following terms used in the specification and claims have the following meanings:

[0079] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, and is preferably a linear alkyl group or a branched alkyl group containing 1 to 10 or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and is particularly preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 5-methylpentyl group, a 6-methylpentyl group, a 7-methylpentyl group, a 8-methylpentyl group, a 9-methylpentyl group, a 10-methylpentyl group, a 11-methylpentyl group, a 12-methylpentyl group, a 13-methylpentyl group, a 14-methylpentyl group, a 15-methylpentyl group, a 16-methylpentyl group, a 17-methylpentyl group, a 18-methylpentyl group, a 21-methylpentyl group, a 22-methylpentyl group, a 23-methylpentyl group, a 24-methylpentyl group, a 25-methylpentyl group, a 26-methylpentyl group, a 27-methylpentyl group, a 28-methylpentyl group, a 29-methylpentyl group, a 30-methylpent Examples of alkyl groups include, but are not limited to, octyl, 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, and various branched chain isomers thereof. 1-10 "Alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1-4 "Alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 4 carbon atoms. 0-8 "Alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 0 to 8 carbon atoms. 0-4"Alkyl groups" include straight chain alkyl groups and branched chain alkyl groups containing 0 to 4 carbon atoms.

[0080] The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0081] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon may contain one or more (preferably one, two or three) double bonds, but does not contain any ring with a completely conjugated π-electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, and preferably contains 3 to 12, 3 to 8 or 3 to 6 carbon atoms, such as "C 3-12 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 12 carbon atoms, and "C 3-6 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, wherein: Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0082] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share one carbon atom (called a spiro atom) between monocyclic rings; these groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a fully conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, and spirocycloalkyl groups include, but are not limited to: [ka]

[0083] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, wherein one or more rings in the system may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated pi-electron system. Depending on the number of constituent rings, fused cycloalkyl groups may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, and fused cycloalkyl groups include, but are not limited to: [ka]

[0084] "Bridged cycloalkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and these groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated pi-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged cycloalkyl groups include, but are not limited to: [ka]

[0085] The ring of the cycloalkyl group may be fused to the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like.

[0086] Cycloalkyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0087] The term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may contain one or more (preferably one, two, or three) double bonds, but which does not contain any ring with a completely conjugated pi-electron system, and in which one or more (preferably one, two, three, or four) ring atoms in the heterocyclic group are nitrogen, oxygen, S(O)(=NH) or S(O) r(where r is an integer of 0, 1, or 2), but does not include a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon atoms, and is preferably a heterocyclic group containing 3 to 12, 3 to 8, 3 to 6, or 5 to 6 ring atoms. For example, a "3- to 6-membered heterocyclic group" is a ring group containing 3 to 6 ring atoms, a "3- to 12-membered heterocyclic group" is a ring group containing 3 to 12 ring atoms, a "5-membered heterocyclic group" is a ring group containing 5 ring atoms, a "5- to 8-membered heterocyclic group" is a ring group containing 5 to 8 ring atoms, and a "5- to 10-membered heterocyclic group" is a ring group containing 5 to 10 ring atoms.

[0088] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0089] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, in which one or more (preferably one, two, three, or four) ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2), with the remaining ring atoms being carbon atoms. These groups may contain one or more double bonds (preferably one, two, or three), but none of the rings has a fully conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are divided into monospiroheterocyclic groups, bisspiroheterocyclic groups, or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to: [ka]

[0090] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, and one or more (preferably one, two, three, or four) rings may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably one, two, three, or four) ring atoms therein are nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings, fused heterocyclic groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and fused heterocyclic groups include, but are not limited to: [ka]

[0091] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, and these groups may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably one, two, three, or four) ring atoms thereof are nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon atoms. Depending on the number of constituent rings, bridged heterocyclic groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged heterocyclic groups include, but are not limited to: [ka]

[0092] The ring of the heterocyclic group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to: [ka]

[0093] Heterocyclic groups may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0094] An "aryl group" or "aromatic ring" is an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aryl group containing 6 to 10, or 6 to 8, or 6 carbon atoms, e.g., "C 6-10 An "aryl group" is an all-carbon aryl group containing 6 to 10 carbon atoms, and "C 6-8 An "aryl group" is an all-carbon aryl group containing 6 to 8 carbon atoms, including, but not limited to, phenyl and naphthyl. The ring of the aryl group may be fused to the ring of a heteroaryl group, heterocyclic group, or cycloalkyl group, where the ring connected to the parent structure is the ring of the aryl group, including, but not limited to: [ka]

[0095] An "aryl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 15R 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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0096] The term "heteroaryl group" refers to a heteroaromatic group containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer of 0, 1, or 2) heteroatoms, preferably 5 to 10, 5 to 8, or 5 to 6 ring atoms. For example, a "5-8-membered heteroaryl group" refers to a heteroaromatic group containing 5 to 8 ring atoms, and a "5-10-membered heteroaryl group" refers to a heteroaromatic group containing 5 to 10 ring atoms, including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The ring of the heteroaryl group may be fused to the ring of an aryl group, heterocyclic group, or cycloalkyl group, where the ring connected to the parent structure is the ring of the heteroaryl group, including, but not limited to: [ka]

[0097] A "heteroaryl group" may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0098] The term "alkenyl group" refers to an alkyl group as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a straight-chain or branched-chain alkenyl group containing 2 to 10 or 2 to 4 carbon atoms, such as "C 2-10 "Alkenyl group" refers to a straight-chain or branched-chain alkenyl group containing 2 to 10 carbon atoms, and "C 2-4The term "alkenyl group" refers to a straight-chain or branched-chain alkenyl group containing 2 to 4 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0099] The "alkenyl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0100] The term "alkynyl group" refers to an alkyl group as defined above, which is composed of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a straight-chain or branched-chain alkynyl group containing 2 to 10 or 2 to 4 carbon atoms. For example, "C 2-10 "Alkynyl group" refers to a straight-chain or branched-chain alkynyl group containing 2 to 10 carbon atoms, and "C 2-4 An "alkynyl group" is a straight-chain or branched-chain alkynyl group containing 2 to 4 carbon atoms, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0101] The "alkynyl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0102] "Alkoxy group" refers to an -O-alkyl group, where alkyl is as defined above, e.g., "C 1-10 "Alkoxy group" is an alkyloxy group containing 1 to 10 carbon atoms, and "C 1-4 An "alkoxy group" is an alkyloxy group containing 1 to 4 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0103] The "alkoxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0104] "Cycloalkoxy group" refers to an -O-cycloalkyl group, where cycloalkyl is as defined above, e.g., "C 3-12 "Cycloalkoxy group" is a cycloalkyloxy group containing 3 to 12 carbon atoms, and "C 3-8 A "cycloalkoxy group" is a cycloalkyloxy group containing 3 to 8 carbon atoms, and cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

[0105] The "cycloalkoxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 , -C 0-8 Alkyl-OR 13 , -C 0-8Alkyl-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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0106] "Heterocycleoxy" refers to an -O-heterocycle group, where heterocycle is as defined above, and heterocycleoxy includes, but is not limited to, azetidinyloxy, oxetanyloxy, azacyclopentyloxy, azacyclohexyloxy, oxacyclohexyloxy, and the like.

[0107] The "heterocyclic oxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R 12 , -C0-8 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 Preferred are groups substituted by one or more (preferably 1, 2, 3 or 4) substituents selected from the group consisting of:

[0108] "C 1-10 Alkanoyl group: C 1-10 It refers to the monovalent atomic group remaining after removing the hydroxyl group from an alkyl acid, and is usually expressed as "C0-9 alkyl-C(O)-". For example, "C1 alkyl-C(O)-" is an acetyl group, "C2 alkyl-C(O)-" is a propionyl group, and "C3 alkyl-C(O)-" is a butyryl or isobutyryl group.

[0109] "C 1-4 " is "C 1-4 "C alkyl group" 0-4 " is "C 0-4 "C alkyl group" 1-8 " is "C 1-8 "C alkyl group" 0-8 " is "C 0-8 "alkyl group" is defined above.

[0110] "-C 0-8Alkyl-S(O) r R 12 " is -S(O) r R 12 The sulfur atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0111] "-C 0-8 Alkyl-OR 13 " is -OR 13 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0112] "-C 0-8 Alkyl-C(O)OR 13 " is -C(O)OR 13 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0113] "-C 0-8 Alkyl-C(O)R 14 " is -C(O)R 14 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0114] "-C 0-8 Alkyl-OC(O)R 14 " is -OC(O)R 14 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0115] "-C 0-8 Alkyl-NR 15 R 16 " is -NR 15 R 16 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8The alkyl group is as defined above.

[0116] "-C 0-8 Alkyl-C(=NR 15 )R 14 " is -C(=NR 15 )R 14 The carbon atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0117] "-C 0-8 Alkyl-N(R 15 )-C(=NR 16 )R 14 " is -N(R 15 )-C(=NR 16 )R 14 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0118] "-C 0-8 Alkyl-C(O)NR 15 R 16 " is -C(O)NR 15 R 16 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0119] "-C 0-8 Alkyl-N(R 15 )-C(O)R 14 " is -N(R 15 )-C(O)R 14 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0120] Halogen-substituted C 1-10"Alkyl group" refers to an alkyl group of 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced by a fluorine, chlorine, bromine, or iodine atom, including, but not limited to, difluoromethyl (-CHF2), dichloromethyl (-CHCl2), dibromomethyl (-CHBr2), trifluoromethyl (-CF3), trichloromethyl (-CCl3), tribromomethyl (-CBr3), and the like.

[0121] Halogen-substituted C 1-10 The term "alkoxy group" refers to an alkoxy group of 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom. Examples include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy groups.

[0122] Deuterium-substituted C 1-10 "Alkyl group" refers to an alkyl group of 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced by a deuterium atom, including, but not limited to, monodeuteromethyl (-CH2D), dideuteromethyl (-CHD2), trideuteromethyl (-CD3), and the like.

[0123] Deuterium-substituted C 1-10 An "alkoxy group" refers to an alkoxy group of 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced with a deuterium atom. Examples include, but are not limited to, monodeuteromethoxy, dideuteromethoxy, trideuteromethoxy, and the like.

[0124] "Halogen" refers to fluorine, chlorine, bromine, or iodine. "EtOAc" refers to ethyl acetate. "PE" refers to petroleum ether. "DMF" refers to dimethylformamide.

[0125] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and where it does not occur, i.e., includes both cases: substituted and unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the 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.

[0126] "Substitution" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. Of course, the substituents are only in their chemically possible positions, and are in accordance with the chemical valence bond theory, so that a person skilled in the art can easily confirm (through experiment or theory) whether the substitution is possible or not. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (e.g., an olefin).

[0127] The term "stereoisomer" refers to an isomer formed by differences in the spatial arrangement of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers formed by the rotation of a single bond are called conformational isomers, sometimes called rotamers. Stereoisomers formed by bond length, bond angles, or the presence of double bonds or rings in the molecule are called configurational isomers, which are further divided into two types. Isomers formed because the double bonds or single bonds of ring carbon atoms cannot freely rotate are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers, and when a compound of the present invention contains a double bond, it may be understood to include the E-form and / or the Z-form unless otherwise specified. Stereoisomers having different optical rotatory powers formed due to the lack of antiaxial symmetry in the molecule are called optical isomers and are divided into R and S configurations. Unless otherwise specified, the "stereoisomer" described in the present invention may be understood to include one or more of the enantiomers, configurational isomers, and conformational isomers.

[0128] The term "pharmaceutically acceptable salt" as used herein 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.

[0129] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, and other components, such as physiologically / pharmaceutically acceptable carriers and excipients, to facilitate administration to a living body and contribute to the absorption of the active ingredients, thereby further exerting biological activity.

[0130] The present invention will be explained in more detail and comprehensively below in conjunction with examples, but the present invention is not limited to the examples in any way.

[0131] The structure of the compounds of the present invention is confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (MeOH-d4), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0132] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 6120 mass spectrometer, and HPLC measurements were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 × 4.6 mm column).

[0133] Thin-layer chromatography silica gel plates used were Yantai Yellow Sea HSGF254 or Qingdao GF254, with a 0.15-0.20 mm diameter for TLC and a 0.4-0.5 mm diameter for product separation and purification. For column chromatography, Yantai Yellow Sea silica gel with a 200-300 mesh diameter was generally used.

[0134] The starting materials in the examples of the present invention are known and commercially available or can be synthesized by or according to methods known in the art.

[0135] Unless otherwise specified, all reactions of this invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and reaction temperatures are in degrees Celsius (°C).

[0136] 1. Manufacturing of intermediates Intermediate A1:N 1 ,N 1 -Dimethyl-N 2 Preparation of -(methyl-d3)ethane-1,2-diamine [ka] Deuterated methylamine hydrochloride (4.9 g, 69.43 mmol) and water (5 mL) were added to a round-bottom flask, and the solution was cooled to -12 °C. Sodium hydroxide (2.78 g, 0.07 mmol) was dissolved in water (4 mL) and added dropwise to the round-bottom flask. The mixture was stirred at -12 °C for 15 minutes. Then, an aqueous solution (4 mL) of 2-chloro-N,N-dimethylethan-1-amine hydrochloride (1 g, 6.94 mmol) was added dropwise to the round-bottom flask. The reaction mixture was stirred at room temperature for 4 hours and cooled to 0 °C. Sodium hydroxide (2.9 g, 0.07 mmol) was dissolved in water (10 mL) and added dropwise to the round-bottom flask. The mixture was extracted with dichloromethane (3 × 7 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure at low temperature to obtain N. 1 ,N 1 -Dimethyl-N 2 -(Methyl-d3)ethane-1,2-diamine was obtained and used directly in the next reaction.

[0137] Preparation of Intermediate A2: 2-((methyl-d3)amino)ethan-1-ol Hydrochloride [ka]

[0138] First step: Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate [ka] To a solution of tert-butyl (2-hydroxyethyl)carbamate (5.3 g, 32.87 mmol) in dichloromethane (80 mL) was added imidazole (3.36 g, 49.31 mmol) and 4-(dimethylamino)pyridine (0.6 g, 4.91 mmol) at room temperature. The mixture was stirred at room temperature for 5 minutes. Then, a solution of chlorodimethyl(2-methylpropan-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. Upon completion of the reaction, the mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to obtain tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (7.5 g, yield: 82%).

[0139] 1 H NMR (CDCl3) δ 4.78 (s, 1H), 3.60 (t, J = 5.2 Hz, 2H), 3.16 (q, J = 5.4 Hz, 2H), 1.39 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H).

[0140] Second step: Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl-d3)carbamate [ka] At 0 °C, sodium bicarbonate (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 min, deuterated iodomethane (1.8 mL, 28.75 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 min. Water and dichloromethane were added for extraction. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was purified by high-performance 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%).

[0141] 1 H NMR (CDCl3) δ 3.65 (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).

[0142] Third step: Synthesis of 2-((methyl-d3)amino)ethan-1-ol hydrochloride [ka] To a solution of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl-d3)carbamate (5.5 g, 18.80 mmol) in tetrahydrofuran (15 mL) was added 4 N hydrochloric acid in dioxane (14 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was distilled under reduced pressure to give 2-((methyl-d3)amino)ethan-1-ol hydrochloride (1.5 g).

[0143] Intermediate A3:N 1 -(4-Methoxybenzyl)-N 2 ,N 2 -Production of dimethylethane-1,2-diamine [ka] N 1 ,N 1- Dimethylethane-1,2-diamine (10 g, 113.4 mmol) and 4-methoxybenz(methyl)aldehyde (18.5 g, 136.1 mmol) were dissolved in dichloromethane (10 mL). To the solution was added acetic acid (0.65 mL, 11.6 mmol) and sodium acetylborohydride (35 g, 170.1 mmol). The reaction was stirred at room temperature for 18 hours. The layers were partitioned between 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 = 4:1] to obtain N 1 -(4-Methoxybenzyl)-N 2 ,N 2 -Dimethylethane-1,2-diamine (16 g, yield: 67%) was obtained. ESI-MS: 209.0 [M+1] + .

[0144] Preparation of Intermediate A4: 1-((2R,4S)-4-fluoropyrrolidin-2-yl)-N,N-dimethylmethanamine [ka]

[0145] First step: Synthesis of 1-(tert-butyl) 2-methyl(2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylate [ka] N,N-Diethyl-1,1,1-trifluoro-14-sulfanylamine (19.7 g, 122.3 mmol) was added to a solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (15.0 g, 61.1 mmol) in dichloromethane (100 mL) in an ice bath. The mixture was stirred for 30 minutes in an ice bath and then at 30 °C for 2 hours. After completion of the reaction, the reaction mixture was slowly poured into saturated sodium bicarbonate solution to quench the reaction, followed by extraction with dichloromethane and phase separation. The organic phase was concentrated and separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give 1-(tert-butyl) 2-methyl(2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (8.20 g, yield: 54.23%).

[0146] 1 H NMR (DMSO-d6) δ 5.31 (dt, J = 52.6, 3.5 Hz, 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 = 24.0 Hz, 9H).

[0147] Second step: Synthesis of (2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid [ka] 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-dicarboxylate (8.2 g, 33.1 mmol) in methanol / tetrahydrofuran / water (20 mL / 20 mL / 20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added, the pH was adjusted to 4-5 with concentrated hydrochloric acid, and the mixture was extracted with dichloromethane and separated. 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] + .

[0148] Third step: Synthesis of tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate [ka] Borane-tetrahydrofuran solution (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) in an ice bath. The mixture was stirred for 30 minutes in an ice bath and then at 75 °C for 1 hour. After completion of the reaction, the reaction mixture was slowly poured into saturated ice water to quench the reaction, followed by extraction with dichloromethane and phase separation. The organic phase was concentrated and separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-70%] to give tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.1 g, yield: 83.4%). ESI-MS: 164.2 [M+1-56] + .

[0149] Fourth step: Synthesis of tert-butyl (2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate [ka] 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-carboxylate (4.6 g, 20.9 mmol) in dichloromethane (50 mL) in an ice bath. The mixture was stirred for 30 minutes in an ice bath. After the reaction was complete, the mixture was partitioned between dichloromethane and water and extracted. The organic phase was concentrated and then separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give tert-butyl (2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (5.2 g, yield: 79.6%). ESI-MS: 212.2 [M+1-100] + .

[0150] Fifth step: Synthesis of tert-butyl (2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylate [ka] In a sealed tube, a solution of tert-butyl (2R,4S)-2-(((ethylsulfonyl)oxy)methyl)-4-fluoropyrrolidine-1-carboxylate (5.2 g, 16.7 mmol) and dimethylamine tetrahydrofuran (50 mL, 100.0 mmol, 2 M) was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was concentrated and separated by high-performance silica gel column chromatography [eluent: dichloromethanol / methanol: 0-10%] to give tert-butyl (2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (3.0 g, yield: 72.9%). ESI-MS: 247.3 [M+1] + .

[0151] 1H NMR (DMSO-d6) δ 5.20 (dt, J = 53.4, 3.7 Hz, 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).

[0152] Sixth step: Synthesis of 1-((2R,4S)-4-fluoropyrrolidin-2-yl)-N,N-dimethylmethanamine [ka] A solution of tert-butyl (2R,4S)-2-((dimethylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (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 completed, the mixture was concentrated to give 1-((2R,4S)-4-fluoropyrrolidin-2-yl)-N,N-dimethylmethanamine hydrochloride (3.0 g, yield: 77.3%). ESI-MS: 147.3 [M+1] + .

[0153] Intermediate B1:N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 Preparation of 1,4-methyl-2-nitrophenyl-1,4-diamine [ka] 4-Fluoro-2-methoxy-5-nitroaniline (1.86 g, 10.0 mmol) was dissolved in 10 mL of N,N-dimethylformamide. 1 ,N 1 ,N 2-trimethylethane-1,2-diamine (1.53 g, 15.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added. 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 mixture was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to obtain N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 2.5 g (yield: 93%) of 1,4-methyl-2-nitrophenyl-1,4-diamine was obtained. ESI-MS: 269.0 [M+1] + .

[0154] Preparation of Intermediate B2: N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide [ka] N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 N-methyl-2-nitrophenyl-1,4-diamine (2.68 g, 10 mmol) and formic acid (20 mL) were added to the reaction flask, and the reaction mixture was stirred at 100°C for 2 hours. The formic acid was removed by distillation under reduced pressure, 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-nitrophenyl)formamide (2.89 g, yield: 93%). ESI-MS: 296.0 [M+1] + .

[0155] Intermediate B3: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 Preparation of 1,4-methyl-2-nitrophenyl-1,4-diamine [ka]

[0156] First step: Synthesis of 2-(difluoromethoxy)-4-fluoro-1-nitrophenyl [ka] To a solution of 5-fluoro-2-nitrophenol (10 g, 63.6 mmol) in N,N-dimethylformamide (100 mL) was added sodium carbonate (20.2 g, 190.9 mmol). The reaction mixture was heated to 90°C, and sodium 2-chloro-2,2-difluoroacetate (34.0 g, 222.8 mmol) was added in several portions, followed by stirring for an additional 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, concentrated, and then separated by column chromatography [eluent: petroleum ether / ethyl acetate: 0-10%] to give 2-(difluoromethoxy)-4-fluoro-1-nitrophenyl (10.3 g, yield: 78%).

[0157] 1 H NMR (CDCl3) δ 7.96 (dd, J = 9.1, 5.6 Hz, 1H), 7.11 - 6.97 (m, 2H), 6.57 (t, J = 72.4 Hz, 1H).

[0158] Second step: Synthesis of 2-(difluoromethoxy)-4-fluoroaniline [ka] To a solution of 2-(difluoromethoxy)-4-fluoro-1-nitrophenyl (10.3 g, 49.7 mmol) in ethanol, 10% palladium on carbon (1.0 g) was added. The mixture was stirred overnight at room temperature with hydrogen gas. Upon completion of the reaction, the mixture was filtered and distilled under reduced pressure to give 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 86% yield). ESI-MS: 178.1 [M+1] + .

[0159] Third step: Synthesis of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline [ka] To a solution of 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 45.7 mmol) in sulfuric acid (40 mL) was added potassium nitrate (5.1 g, 50.3 mmol) in an ice bath in several portions. The reaction was stirred in the ice bath for 0.5 hours, then allowed to warm to room temperature and stirred for 2 hours. 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 purified by high-performance silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-15%] to give 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (8.0 g, yield: 77%).

[0160] 1 H NMR (CDCl3) δ 7.49 (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).

[0161] Fourth step: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 Synthesis of 1,4-methyl-2-nitrophenyl-1,4-diamine [ka] A solution of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (1.0 g, 4.5 mmol) in acetonitrile (30 mL) was 1 ,N 1 ,N 2 1,2-Trimethylethane-1,2-diamine (690 mg, 6.7 mmol) and potassium carbonate (1.2 g, 9.0 mmol) were added. The reaction mixture was stirred at 80°C for 3 hours. After removing the solvent, the mixture was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to give 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N1 1.25 g (yield: 83%) of 1,4-methyl-2-nitrophenyl-1,4-diamine was obtained. ESI-MS: 305.2 [M+1] + .

[0162] Intermediates B4 to B5 were prepared by referring to the method for preparing intermediate B3: sodium 2-chloro-2,2-difluoroacetate in the first step was replaced with deuterated iodomethane, iodoethane, or isoiodopropane, and the reaction conditions were changed to stirring at 37°C for 18 hours, with the remaining steps remaining the same. Intermediate B6 was prepared by referring to the first to third steps of the method for preparing intermediate B3.

[0163] [Table 1]

[0164] Intermediate B7:N 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N 1 Preparation of 1,4-methyl-2-nitrophenyl-1,4-diamine [ka]

[0165] First step: Synthesis of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate [ka] 4-Fluoro-2-methoxy-5-nitroaniline (1 g, 5.4 mmol) was dissolved in 1,4-dioxane (30 mL), di-tert-butyl dicarbonate (2.2 g, 10.8 mmol) was added, and the mixture was stirred at 120 °C overnight. The solvent was removed, and the residue was subjected to column chromatography to give tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate (1.3 g, yield: 84.4%). ESI-MS: 287.2 [M+1] + .

[0166] Second step: Synthesis of tert-butyl (4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate [ka] To a solution of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate (328 mg, 1.15 mmol) in 1,4-dioxane (10 mL), 2-(methylamino)ethan-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 removing the solvent, the product was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to give tert-butyl (4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate (390 mg, yield: 90.7%). ESI-MS: 342.0 [M+1] + .

[0167] Third step: Synthesis of 2-((4-((tert-butoxycarbonyl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate [ka] A solution of t-butyl-butyl (4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)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 hours. After removing the solvent, the residue was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to give 2-((4-((tert-butoxycarbonyl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate (480 mg, 100% yield). ESI-MS: 420.0 [M+1] + .

[0168] Fourth step: Synthesis of tert-butyl (4-((2-(di(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate [ka] To a sealed tube was added 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). The reaction mixture was stirred at 60°C for 5 hours. After removing the solvent, the residue was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to give tert-butyl (4-((2-(di(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate (293 mg, yield: 68.1%). ESI-MS: 375.2 [M+1] + .

[0169] Fifth step:N 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N1 Synthesis of 1,4-methyl-2-nitrophenyl-1,4-diamine [ka] To a solution of tert-butyl (4-((2-(di(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate (293 mg, 0.78 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. After removing the solvent, N 1 -(2-(di(methyl-d3)amino)ethyl)-5-methoxy-N 1 180 mg of 1,4-methyl-2-nitrophenyl-1,4-diamine (yield: 83.8%) was obtained. ESI-MS: 275.1 [M+1] + .

[0170] Intermediate B8:N 1 Preparation of -(2-(dimethylamino)ethyl)-5-((4-methoxybenzyl)oxy)-2-nitrophenyl-1,4-diamine [ka]

[0171] First step: Synthesis of 2-amino-5-fluoro-4-nitrophenol [ka] 2-Amino-5-fluorophenol (5.08 g, 39.96 mmol) was dissolved in dichloromethane and cooled to -10 °C. A mixture of 63% mass fraction concentrated nitric acid (4.44 g, 47.96 mmol) and 98% mass fraction concentrated 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 by adding saturated sodium sulfate solution, diluted with ethyl acetate, and separated. The organic phase was washed twice with water and once with saturated brine. The organic phase was dried and distilled under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain 2-amino-5-fluoro-4-nitrophenol (1.4 g, 18.93% yield). ESI-MS: 190.0 [M+NH4] + .

[0172] Second step: Synthesis of N-(4-fluoro-2-hydroxy-5-nitrophenyl)acetamide [ka] 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 was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched by adding water, and the solid was collected by filtration and dried to give N-(4-fluoro-2-hydroxy-5-nitrophenyl)acetamide (580 mg, 88.57% yield). ESI-MS: 232.0 [M+NH4] + .

[0173] Third step: Synthesis of N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide [ka] 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 to complete the reaction. The reaction mixture was washed with saturated brine, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (720 mg, yield: 43.74%). ESI-MS: 352.0 [M+NH4] + .

[0174] Fourth step: Synthesis of N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide [ka] To a solution of N-(4-fluoro-2-((4-methoxybenzyl)oxy)-5-nitrophenyl)acetamide (720 mg, 2.15 mmol) in 1,4-dioxane (30 mL), 1 ,N 1 ,N 2 N-trimethylethane-1,2-diamine (0.65 mL, 4.31 mmol) and diisopropylethylamine (0.65 mL, 4.31 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. After removing the solvent, the residue was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] 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] + .

[0175] Fifth step:N 1Synthesis of -(2-(dimethylamino)ethyl)-5-((4-methoxybenzyl)oxy)-2-nitrophenyl-1,4-diamine [ka] 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 completed, the mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain N 1 -(2-(dimethylamino)ethyl)-5-((4-methoxybenzyl)oxy)-2-nitrophenyl-1,4-diamine (150 mg, yield: 24.9%) was obtained. ESI-MS: 361.2 [M+1] + .

[0176] Intermediate B9:N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Preparation of 3-methyl-3-nitropyridine-2,5-diamine [ka]

[0177] First step: Synthesis of 6-bromo-2-methoxy-3-nitropyridine [ka] Sodium methanolate (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) in an ice bath. The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, concentrated, and then 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] + .

[0178] Second step: Synthesis of 6-bromo-2-methoxypyridin-3-amine [ka] To a solution of 6-bromo-2-methoxy-3-nitropyridine (13.9 g, 60.1 mmol) in ethanol / water (2:1) was added iron powder (26.9 g, 480.8 mmol) and ammonium chloride (25.9 g, 480.8 mmol). The reaction mixture was stirred at approximately 90°C for 3 hours. The mixture was partitioned between dichloromethane and water. The organic phase was concentrated and then separated by column chromatography (petroleum ether:ethyl acetate (3:1)) to give 6-bromo-2-methoxypyridin-3-amine (9.1 g, 75% yield). ESI-MS: 203.1 [M+1] + .

[0179] 1 H NMR (DMSO-d6) δ 6.89 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.10 (s, 2H), 3.84 (s, 3H).

[0180] Third step: Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)acetamide [ka] To a solution of 6-bromo-2-methoxypyridin-3-amine (9.1 g, 44.8 mmol) in dichloromethane (200 mL) was added triethylamine (6.7 g, 67.2 mmol) and acetyl chloride (3.8 g, 49.2 mmol) in an ice bath. The reaction mixture was stirred for 1 hour in an ice bath. The mixture was partitioned between dichloromethane and water, and the organic phase was concentrated and then 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 in the next step.

[0181] Fourth step: Synthesis of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide [ka] To a solution of N-(6-bromo-2-methoxypyridin-3-yl)acetamide (9.5 g, 38.9 mmol) in trifluoroacetic anhydride (80 mL) was added concentrated nitric acid (65%, 46.6 mmol) in an ice bath. The reaction was stirred in an ice bath for 1 hour. The reaction solution was slowly poured into ice water and stirred for 1 hour. The solid precipitated, filtered with suction, and the filter cake was dried to give N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (11.5 g, 100% yield). ESI-MS: 290.1 ​​[M+1] + .

[0182] 1 H NMR (DMSO-d6) δ 9.90 (s, 1H), 9.12 (s, 1H), 4.06 (s, 3H), 2.16 (s, 3H).

[0183] Fifth step (intermediate B9-1): Synthesis of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide [ka] A solution of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 3.4 mmol) in acetonitrile (20 mL) was 1 ,N 1 ,N 2 N-trimethylethane-1,2-diamine (520 mg, 5.1 mmol) was added. The reaction mixture was stirred at 80°C for 1 hour. After removing the solvent, the residue 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] + .

[0184] Sixth step: N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Synthesis of 2,5-methyl-3-nitropyridine-2,5-diamine [ka] To a solution of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (756 mg, 2.4 mmol) in methanol (10 mL) was added concentrated hydrochloric acid (37%, 1.5 mL, 18 mmol). The reaction was stirred at 60 °C for 5 h. The layers were partitioned with saturated sodium bicarbonate solution and dichloromethane. The organic phase was concentrated and then diluted with N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 645 mg of 100% methyl-3-nitropyridine-2,5-diamine was obtained. ESI-MS: 270.3 [M+1] + .

[0185] Intermediates B10-1 to B14-1 were produced by referring to the production method of intermediate B9-1: [Table 2]

[0186] Intermediates B10 to B14 were produced by referring to the production method of intermediate B9: [Table 3]

[0187] Preparation of Intermediate B15: 2-Cyclopropoxy-4-fluoro-5-nitroaniline [ka]

[0188] First step: Synthesis of 2-cyclopropoxy-4-fluoroaniline [ka] To a solution of 2,4-difluoro-1-nitrophenyl (4.0 g, 25.14 mmol) in tetrahydrofuran (80 mL), cyclopropanol (1.46 g, 25.14 mmol) and cesium carbonate (8.19 g, 25.14 mmol) were added. The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the mixture 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 give 2-cyclopropoxy-4-fluoro-1-nitrophenyl. The resulting 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 mixture was filtered through diatomaceous earth. The resulting solution was partitioned between ethyl acetate and water. The organic phase was washed 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] + .

[0189] Second step: Synthesis of N-(2-cyclopropoxy-4-fluorophenyl)acetamide [ka] 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) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. After completion of the reaction, the mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate. The organic phase obtained after separation was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to give N-(2-cyclopropoxy-4-fluorophenyl)acetamide (1.55 g, 95% yield). ESI-MS: 210.0 [M+1] + .

[0190] Third step: Synthesis of N-(2-cyclopropoxy-4-fluoro-5-nitrophenyl)acetamide [ka] N-(2-cyclopropoxy-4-fluorophenyl)acetamide (1.55 g, 7.38 mmol) and trifluoroacetic anhydride (16 mL) were added to a 250 mL single-neck flask and cooled to -10 °C in an ice-salt bath. Concentrated nitric acid (0.8 mL, 11.8 mmol) was added dropwise, controlling the temperature below -5 °C. After the addition was completed, the reaction mixture was stirred at -10 °C for 1.5 hours. The reaction mixture was slowly poured into 90 mL of ice water to precipitate a solid. 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, 33% yield). ESI-MS: 255.0 [M+1] + .

[0191] Fourth step: Synthesis of 2-cyclopropoxy-4-fluoro-5-nitroaniline [ka] To a solution of N-(2-cyclopropoxy-4-fluoro-5-nitrophenyl)acetamide (138 mg, 0.54 mmol) in methanol (10 mL) was added concentrated hydrochloric acid (1 mL). The reaction mixture was stirred at 60°C for 3 hours. After completion of the reaction, the solvent was removed, dichloromethane (10 mL) was added, and the pH was adjusted to basic 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. Filtration and removal of the solvent gave 2-cyclopropoxy-4-fluoro-5-nitroaniline (85 mg, 73% yield). ESI-MS: 213.0 [M+1] + .

[0192] Preparation of Intermediate C1: 3,3-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0193] First step: Synthesis of 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl)malonate [ka] At 0°C, tert-butyl ethyl malonate (44.52 g, 236.5 mmol) was slowly added dropwise to a suspension of sodium hydride (9.46 g, 236.5 mmol) in tetrahydrofuran (200 mL). 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. Upon completion, the mixture was cooled to 0°C and quenched by the slow addition of 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 purified by high-performance silica gel column chromatography (eluent: ethyl acetate / petroleum ether: 0-50%) to give 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl)malonate (32.7 g, yield: 66.8%). ESI-MS: 255.0 [M-55] + .

[0194] Second step: Synthesis of ethyl 2-(3-nitropyridin-2-yl)acetate [ka] 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl)malonate (32.7 g, 84.3 mmol) was added with trifluoroacetic acid (18.8 mL, 252.9 mmol). The mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and distilled under reduced pressure to remove trifluoroacetic acid. Saturated sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to give ethyl 2-(3-nitropyridin-2-yl)acetate (17.7 g, yield: 91.9%). ESI-MS: 211.0 [M+1] + .

[0195] Third step: Synthesis of ethyl 2-methyl-2-(3-nitropyridin-2-yl)propionate [ka] 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, iodomethane (6.25 g, 44 mmol), 18-crown-6 (0.39 g, 1.47 mmol), and sodium hydride (1.2 g, 29.4 mmol) were added slowly. The mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, 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 purified by high-performance 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] + .

[0196] Fourth step: Synthesis of 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] To a solution of ethyl 2-methyl-2-(3-nitropyridin-2-yl)propionate (3.2 g, 13.4 mmol) in ethanol (20 mL) was added ammonium formate (3.4 g, 53.7 mmol) and 10% palladium on carbon (300 mg), and the mixture was stirred at 90 °C for 2 hours. After completion of the reaction, the reaction mixture 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 the mixture was distilled under reduced pressure to obtain the crude product, 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.72 g, 79% yield), which was used directly in the next reaction. ESI-MS: 163.0 [M+1] + .

[0197] Fifth step: Synthesis of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 3,3-Dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.22 g, 7.53 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (4 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50 °C for 3 hours. Upon completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no further bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.2 g, 100% yield). ESI-MS: 149.0 [M+1] + .

[0198] Intermediate C2: Preparation of 1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0199] Step 1: Synthesis of ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylate [ka] 2-(3-Nitropyridin-2-yl)acetate (2.18 g, 9.85 mmol) was dissolved in dimethyl sulfoxide (50 mL), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (4.28 g, 11.82 mmol) was added thereto. The mixture was stirred at room temperature for 2 minutes, and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (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, the solvent was removed, and the residue was purified by column chromatography to give ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylate (2.05 g, 82.79% yield). ESI-MS: 236.9 [M+1]. + .

[0200] Second step: Synthesis of ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylate [ka] To a solution of ethyl 1-(3-nitropyridin-2-yl)cyclopropane-1-carboxylate (2.05 g, 8.24 mmol) in ethanol (20 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylate (1.70 g, 100% yield), which was used directly in the next reaction. ESI-MS: 206.9 [M+1] + .

[0201] Third step: Synthesis of spiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] To a solution of ethyl 1-(3-aminopyridin-2-yl)cyclopropane-1-carboxylate (1.7 g, 8.24 mmol) in ethanol (20 mL) was added 36% concentrated hydrochloric acid (0.5 mL), and the mixture was stirred at 60 °C for 18 hours. After completion of the reaction, the reaction mixture was neutralized with sodium hydroxide solution, washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by column chromatography to give spiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (0.4 g, yield: 28.8%). ESI-MS: 160.9 [M+1] + .

[0202] Fourth step: Synthesis of 1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 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) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (3 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50 °C for 3 hours. Upon completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no further 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, 89.6% yield). ESI-MS: 147.0 [M+1] + .

[0203] Intermediate C3: Preparation of 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0204] First step: Synthesis of spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] Sodium hydride (3.0 g, 74.5 mmol) and hexamethylphosphoric triamide (12 mL) were dissolved in anhydrous N,N-dimethylformamide (60 mL). To the reaction mixture was added 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). The reaction mixture was stirred under nitrogen gas protection at 0 °C for 1 h. Upon completion, the mixture was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL). The organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated, and the residue was separated by high-performance 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] + .

[0205] Second step: Synthesis of 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 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 gas protection to complete the reaction. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated, and the residue was separated by high-performance silica gel column chromatography [petroleum ether / ethyl acetate = 2:1] to give 1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (210 mg, 95%). ESI-MS: 161.0 [M+1] + .

[0206] Preparation of Intermediate C4: 5'-(1-methyl-1H-pyrazolyl-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0207] First step: Synthesis of 5'-bromo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 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. Upon completion of the reaction, the solvent was removed by vacuum distillation, and the residue was separated by high-performance 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] + .

[0208] Second step: Synthesis of 5'-(1-methyl-1H-pyrazolyl-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka] A reaction flask was charged with 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-dioxaborolan-2-yl)-1H-pyrazolyl (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). The mixture was purged with nitrogen gas three times and heated to 110 °C under nitrogen protection for 16 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by high-performance silica gel column chromatography (eluent: ethyl acetate / petroleum ether: 0-50%) to give 5'-(1-methyl-1H-pyrazolyl-4-yl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (70 mg, yield: 40.2%). ESI-MS: 241.0 [M+1] + .

[0209] Preparation of Intermediate C5: 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0210] First step: Synthesis of 2-iodo-6-methyl-N-(2-methallyl)pyridin-3-amine [ka] Potassium tert-butoxide (1.14 g, 10.2 mmol) was added to a solution of 2-iodo-6-methylpyridin-3-amine (2 g, 8.5 mmol) in tetrahydrofuran (40 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes. 3-Bromo-2-methylprop-1-ene (1.27 g, 9.4 mmol) was then slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 2-iodo-6-methyl-N-(2-methallyl)pyridin-3-amine (1.46 g, yield: 59%). ESI-MS: 288.9 [M+1] + .

[0211] Second step: Synthesis of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 2-iodo-6-methyl-N-(2-methallyl)pyridin-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). The mixture was purged with nitrogen gas three times and heated to 120 °C under nitrogen gas protection and stirred for 1 h. The reaction mixture was filtered, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by high-performance 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, 81% yield). ESI-MS: 163.0 [M+1] + .

[0212] Intermediate C6: Preparation of 5-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0213] First step: Synthesis of 6-chloro-2-iodopyridin-3-amine [ka] 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. Upon completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance 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] + .

[0214] Second step: Synthesis of 6-chloro-2-iodo-N-(2-methallyl)pyridin-3-amine [ka] Potassium tert-butoxide (8.2 g, 73.1 mmol) was added to a solution of 6-chloro-2-iodopyridin-3-amine (15.5 g, 60.9 mmol) in tetrahydrofuran (200 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes. 3-Bromo-2-methylprop-1-ene (9.9 g, 73.1 mmol) was then slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 6-chloro-2-iodo-N-(2-methallyl)pyridin-3-amine (15.5 g, yield: 82.5%). ESI-MS: 308.8 [M+1] + .

[0215] Third step: Synthesis of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 6-chloro-2-iodo-N-(2-methallyl)pyridin-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). The mixture was purged with nitrogen gas three times, heated to 120 °C under nitrogen gas protection, and stirred for 1 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by high-performance 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] + .

[0216] Fourth step: Synthesis of 5-cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 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). The mixture was purged with nitrogen gas three times and heated to 110°C under nitrogen protection and stirred for 6 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by high-performance 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] + .

[0217] Preparation of Intermediate C7: 3,3-dimethyl-5-(1-methyl-1H-pyrazolyl-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 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-dioxaborolan-2-yl)-1H-pyrazolyl (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). The mixture was purged with nitrogen gas three times and heated to 110 °C under nitrogen protection and stirred for 16 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by high-performance silica gel column chromatography (eluent: ethyl acetate / petroleum ether: 0-50%) to give 3,3-dimethyl-5-(1-methyl-1H-pyrazolyl-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (125 mg, yield: 35.8%). ESI-MS: 229.0 [M+1] + .

[0218] Intermediate C8: Preparation of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0219] First step: Synthesis of 6-bromo-2-iodopyridin-3-amine [ka] N-iodosuccinimide (2.70 g, 12.0 mmol) was added to a solution of 6-bromopyridin-3-amine (1.73 g, 10 mmol) in N,N-dimethylformamide (50 mL) at room temperature. The mixture was stirred overnight at room temperature. Upon completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance 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] + .

[0220] Second step: Synthesis of 6-bromo-2-iodo-N-(2-methallyl)pyridin-3-amine [ka] To a solution of 6-bromo-2-iodopyridin-3-amine (2.09 g, 7.0 mmol) in tetrahydrofuran (50 mL) at room temperature, potassium tert-butoxide (8.4 mL, 8.4 mmol, 1 M / mL) was added. The mixture was stirred at room temperature for 15 minutes. 3-Bromo-2-methylprop-1-ene (1.04 g, 7.7 mmol) was then slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 6-bromo-2-iodo-N-(2-methallyl)pyridin-3-amine (2.1 g, yield: 69.8%). ESI-MS: 352.8, 354.8 [M+1] + .

[0221] Third step: Synthesis of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 6-bromo-2-iodo-N-(2-methallyl)pyridin-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). The mixture was purged with nitrogen gas three times, heated to 120 °C under nitrogen gas protection, and stirred for 1 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by high-performance 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] + .

[0222] Preparation of Intermediate C9: 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0223] First step: Synthesis of 2-iodo-N-(2-methallyl)-6-(trifluoromethyl)pyridin-3-amine [ka] Potassium tert-butoxide (933 mg, 8.33 mmol) was added to a solution of 2-iodo-6-(trifluoromethyl)pyridin-3-amine (2 g, 6.94 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes. 3-Bromo-2-methylprop-1-ene (1.17 g, 8.33 mmol) was then slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-20%] to give 2-iodo-N-(2-methallyl)-6-(trifluoromethyl)pyridin-3-amine (888 mg, yield: 37%). ESI-MS: 342.9 [M+1] + .

[0224] Second step: Synthesis of 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 2-iodo-N-(2-methallyl)-6-(trifluoromethyl)pyridin-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). The mixture was purged with nitrogen gas three times, heated to 100 °C under nitrogen gas protection, and stirred for 1 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by high-performance 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] + .

[0225] Intermediate C10: Preparation of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0226] First step: Synthesis of 2-bromo-6-fluoro-N-(2-methallyl)pyridin-3-amine [ka] To a solution of 2-bromo-6-fluoropyridin-3-amine (1.91 g, 10.0 mmol) in tetrahydrofuran (50 mL) at room temperature, potassium tert-butoxide (12 mL, 12.0 mmol, 1 M / mL) was added. The mixture was stirred at room temperature for 15 minutes. 3-Bromo-2-methylprop-1-ene (1.48 g, 11.0 mmol) was then slowly added dropwise to the mixture. The reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-10%] to obtain 2-bromo-6-fluoro-N-(2-methallyl)pyridin-3-amine (1.7 g, yield: 69%). ESI-MS: 244.8 [M+1] + .

[0227] Second step: Synthesis of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 2-bromo-6-fluoro-N-(2-methallyl)pyridin-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). The mixture was purged with nitrogen gas three times and heated to 100 °C under nitrogen gas protection and stirred for 5 h. The reaction mixture was filtered, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by high-performance 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, 51% yield). ESI-MS: 167.0 [M+1] + .

[0228] Preparation of Intermediate C11: 3,3-Dimethyl-1,2,3,5,6,7-hexahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridine [ka]

[0229] First step: Synthesis of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one [ka] At 0 °C, nitric acid (65% mass fraction, 5.4 g, 55.6 mmol) was slowly added dropwise to a solution of 1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one (450 mg, 2.5 mmol) in concentrated sulfuric acid (98% mass fraction, 30 mL). The mixture was stirred at 0 °C for 1 hour, poured slowly into ice water, stirred for 1 hour, 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] + .

[0230] Second step: Synthesis of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine [ka] To a solution of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopentadieno[b]pyridin-2-one (2.5 g, 13.9 mmol) in acetonitrile (50 mL) was added phosphorus oxychloride (6.4 g, 41.6 mmol) and triethylbenzylammonium chloride (1.9 g, 7.0 mmol). The mixture was stirred at 80 °C for 1 h, concentrated under reduced pressure to remove the solvent, and the residue was poured slowly into ice water and stirred for 30 min. Extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine (985 mg, 36.0% yield). ESI-MS: 198.9 [M+1] + .

[0231] Third step: Synthesis of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)malonate [ka] To a solution of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridine (814 mg, 5.1 mmol) in dimethyl sulfoxide (10 mL) was added sodium hydride (220 mg, 5.5 mmol) 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. The mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-30%] to give diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)malonate (409 mg, yield: 30.0%). ESI-MS: 323.0 [M+1] + .

[0232] Fourth step: Synthesis of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)acetate [ka] 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) was added water (0.91 mL, 5.1 mmol) and lithium chloride (267 mg, 6.4 mmol). The mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by high-performance 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] + .

[0233] Fifth step: Synthesis of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate [ka] 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, iodomethane (300 mg, 2.1 mmol), 18-crown-6 (26 mg, 0.1 mmol), and sodium hydride (88 mg, 2.2 mmol) were added slowly. The mixture was stirred at 0°C for 1 hour. Upon completion of the reaction, 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 high-performance 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] + .

[0234] Sixth step: Synthesis of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one [ka] To a solution of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)propionate (150 mg, 0.54 mmol) in ethanol (5 mL), ammonium formate (272 mg, 4.3 mmol) and 10% palladium on carbon (50 mg) were added, and the mixture was stirred at 90 °C for 16 hours. Upon completion of the reaction, the reaction mixture 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 the mixture was distilled under reduced pressure to obtain the crude product, 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one, which was used directly in the next reaction. ESI-MS: 203.0 [M+1] + .

[0235] Seventh step: Synthesis of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridine [ka] The crude 3,3-dimethyl-3,5,6,7-tetrahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridin-2(1H)-one was dissolved in tetrahydrofuran (5 mL) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (2 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the reaction was quenched with sodium sulfate decahydrate until no further foaming occurred. The mixture was filtered, and the filtrate was distilled under reduced pressure to give crude 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopentadieno[b]pyrrolo[2,3-e]pyridine. ESI-MS: 189.0 [M+1] + .

[0236] Intermediate C12: Preparation of 5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0237] First step: Synthesis of 1-(tert-butyl) 3-ethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate [ka] At 0°C, 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). 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. Upon completion, the mixture was cooled to 0°C and 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 purified by high-performance silica gel column chromatography (eluent: ethyl acetate / petroleum ether: 0-20%) to give 1-(tert-butyl) 3-ethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate (41 g, yield: 73.3%). ESI-MS: 325.0 [M+1] + .

[0238] Second step: Synthesis of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate [ka] 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 mixture 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 distilled under reduced pressure. The crude product was separated by high-performance 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] + .

[0239] Third step: Synthesis of ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate [ka] To a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (22 g, 95.4 mmol) in methanol (150 mL) was added 10% palladium on carbon (3.0 g). The mixture was stirred overnight at room temperature with hydrogen gas. Upon completion of the reaction, the mixture was filtered and distilled under reduced pressure to give ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate (17.5 g, 82% yield). ESI-MS: 195.0 [M+1] + .

[0240] Fourth step: Synthesis of 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] 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 basicity with saturated sodium bicarbonate and extracted several times with dichloromethane:methanol (10:1). The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by high-performance 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] + .

[0241] Fifth step: Synthesis of 5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] Sodium hydride (674.9 mg, 16.8 mmol) was dissolved in N,N-dimethylformamide (20 mL) and hexamethylphosphoric triamide (2 mL). The solution was cooled to 0 °C, and 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. Upon completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by high-performance 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] + .

[0242] Sixth step: Synthesis of 5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 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) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (1.7 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50 °C for 2 hours. Upon completion of the reaction, the reaction was quenched with sodium sulfate decahydrate until no further 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, 76% yield). ESI-MS: 175.0 [M+1] + .

[0243] Preparation of Intermediate C13: 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2,2-d2 [ka]

[0244] First step: Synthesis of ethyl 2-methyl-2-(6-methyl-3-nitropyridin-2-yl)propionate [ka] 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, iodomethane (43.68 g, 307.7 mmol), 18-crown-6 (0.39 g, 1.47 mmol), and sodium hydride (10.3 g, 256.4 mmol) were added slowly. The mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, 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 purified by high-performance 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] + .

[0245] Second step: Synthesis of 3,3,5-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] 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) was added 10% palladium-carbon (300 mg), and the mixture was stirred under a hydrogen gas atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated, and the residue was dissolved in acetic acid (50 mL) and reacted at 90 °C overnight. After completion of the reaction, the mixture was distilled under reduced pressure to obtain 3,3,5-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4.0 g, 97% yield), which was used directly in the next reaction. ESI-MS: 163.0 [M+1] + .

[0246] Third step: Synthesis of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2,2-d2 [ka] 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. Lithium aluminum deuteride (0.43 g, 10.2 mmol) was added to the solution. The mixture was stirred at 50 °C for 2 h. Upon completion of the reaction, the reaction was quenched with sodium sulfate decahydrate until no further foaming occurred. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. This was then separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to obtain 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2,2-d2 (0.49 g, 87% yield). ESI-MS: 165.0 [M+1] + .

[0247] Intermediate C14: Preparation of 5-methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0248] Step 1: Synthesis of ethyl 2-(methyl-d3)-2-(6-methyl-3-nitropyridin-2-yl)propionate-3,3,3-d3 [ka] To a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (4 g, 17.84 mmol) in N,N-dimethylformamide (30 mL) was added deuterated iodomethane (19.16 mL, 307.73 mmol), 18-crown-6 (0.47 g, 1.78 mmol), and sodium hydride (1.78 g, 44.60 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by high-performance 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] + .

[0249] Second step: Synthesis of 5-methyl-3,3-di(methyl-d3)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] 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), ammonium formate (3.4 g, 53.7 mmol) and 10% palladium on carbon (300 mg) were added, and the mixture was stirred at 90 °C for 2 hours. Upon completion of the reaction, the reaction mixture 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, 88.6% yield), which was used directly in the next reaction. ESI-MS: 183.0 [M+1] + .

[0250] Third step: Synthesis of 5-methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 5-Methyl-3,3-di(methyl-d3)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (750 mg, 4.12 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (2 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50 °C for 3 hours. Upon completion of the reaction, the reaction was quenched with sodium sulfate decahydrate until no further bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 5-methyl-3,3-di(methyl-d3)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (692 mg, 89.9% yield). ESI-MS: 169.0 [M+1] + .

[0251] Intermediate C15: Preparation of 5'-methyl-1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0252] Step 1: Synthesis of ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate [ka] Ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (4.9 g, 21.8 mmol) was dissolved in dimethyl sulfoxide (30 mL), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (7.92 g, 21.8 mmol) was added. The mixture was stirred at room temperature for 10 minutes. 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (9.8 mL, 65.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL). The organic phase was concentrated, and the residue was separated by high-performance silica gel column chromatography [petroleum ether / ethyl acetate = 3 / 1] to give ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate (5.2 g, 95%). ESI-MS: 251.0 [M+1] + .

[0253] Second step: Synthesis of 5'-methylspiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] Ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate (5.2 g, 20.8 mmol) was dissolved in ethanol (100 mL), palladium on carbon (500 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. Concentrated hydrochloric acid (1 mL) was then added and the mixture was heated and stirred for 18 hours to complete the reaction. The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated, and the residue was separated by high-performance silica gel column chromatography [petroleum ether / ethyl acetate = 1 / 1] to give 5'-methylspiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (3.5 g, 96% yield). ESI-MS: 175.0 [M+1] + .

[0254] Third step: Synthesis of 5'-methyl-1',2'-dihydrospiro(cyclopropane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 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 h under nitrogen gas protection to complete the reaction. The reaction mixture was slowly quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated. The residue was purified by high-performance 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% yield). ESI-MS: 161.0 [M+1] + .

[0255] Preparation of Intermediate C16: 3,3-Difluoro-5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka]

[0256] First step: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-formamide [ka] 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-methylimidazole (6.58 g, 80.2 mmol) were dissolved in acetonitrile (150 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (9.00 g, 32.08 mmol) was added, and the mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by high-performance silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0-30%] to give N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-formamide (7.8 g, yield: 95%). ESI-MS: 304.8 [M+1] + .

[0257] Second step: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-formamide [ka] To a solution of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-formamide (3.0 g, 9.8 mmol) in acetonitrile (50 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.01 mL, 14.75 mmol) and potassium carbonate (4.08 g, 29.5 mmol). The mixture was stirred at 90 °C for 18 h. Upon completion of the reaction, the mixture was filtered and distilled under reduced pressure. The crude product was separated by high-performance 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-formamide (3.8 g, 90% yield). ESI-MS: 425.0 [M+1] + .

[0258] Third step: Synthesis of 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] To a solution of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-formamide (3.2 g, 7.5 mmol) in dioxane (50 mL), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (512 mg, 0.7 mmol) and sodium tert-butoxide (1.45 g, 15.0 mmol) were added, and the mixture was stirred at 100°C for 5 hours under nitrogen gas protection. Upon completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by high-performance 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]pyridin)-2'(1'H)-one (2.0 g, yield: 77%). ESI-MS: 345.0 [M+1] + .

[0259] Fourth step: Synthesis of 3,3-difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one [ka] 3,3-Difluoro-1'-(4-methoxybenzyl)-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (1.8 g, 5.2 mmol) was dissolved in dichloromethane (3 mL), and trifluoromethanesulfonic acid (3.5 mL) was added to the solution. The mixture was stirred at room temperature overnight. Upon completion of the reaction, the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by high-performance silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to give 3,3-difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridin)-2'(1'H)-one (1.1 g, yield: 93%). ESI-MS: 225.0 [M+1] + .

[0260] Fifth step: Synthesis of 3,3-difluoro-5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) [ka] 3,3-Difluoro-5'-methylspiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (250 mg, 1.1 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. A solution of lithium aluminum hydride in tetrahydrofuran (1.3 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50 °C for 2 hours. Upon completion of the reaction, the reaction was quenched with sodium sulfate decahydrate until no further bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to give 3,3-difluoro-5'-methyl-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine) (250 mg, 100% yield). ESI-MS: 211.0 [M+1] + .

[0261] Preparation of Intermediate C17: 5,6-Difluoro-3,3-dimethyldihydroindole [ka]

[0262] First step: Synthesis of 5,6-difluoro-3,3-dimethyldihydroindol-2-one [ka] To a suspension of 5,6-difluorodihydroindol-2-one (5.0 g, 29.5 mmol) and lithium chloride (6.2 g, 148 mmol) in tetrahydrofuran (100 mL) at -78 °C, 2.5 M n-butyllithium solution (59.2 mL, 148 mmol) was slowly added dropwise. The reaction was stirred at -78 °C for 30 minutes, and then iodomethane (21.0 g, 148 mmol) was added. The reaction was continued to stir at -78 °C for 30 minutes and then at room temperature for 2 hours. The mixture was partitioned with 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 column chromatography [petroleum ether / ethyl acetate = 5:1] to give 5,6-difluoro-3,3-dimethyldihydroindol-2-one (3.6 g, 61% yield). ESI-MS: 198.0 [M+1] + .

[0263] Second step: Synthesis of 5,6-difluoro-3,3-dimethyldihydroindole [ka] To a solution of 5,6-difluoro-3,3-dimethyldihydroindol-2-one (3.6 g, 18 mmol) in tetrahydrofuran (80 mL) was added a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (28.8 mL, 72 mmol). The mixture was stirred at 50°C for 3 hours. The mixture was quenched with sodium sulfate decahydrate and filtered. The organic phase was concentrated and then 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]+ .

[0264] 1 H NMR (DMSO-d6) δ 7.03 (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).

[0265] 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-carboxylate [ka] Isopropyl 2,4-dichloropyrimidine-5-carboxylate (147.8 mg, 0.63 mmol) was dissolved in isopropanol (5 mL) at room temperature, and 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) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours using a microwave oven. After completion of the reaction, the solvent was removed, and the residue was separated by silica gel column chromatography [petroleum ether:ethyl acetate = 4:1] to obtain isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (100 mg, yield: 49.2%). ESI-MS: 361.0 [M+1] + .

[0266] Intermediates D2 to D19 were produced by referring to the production method of intermediate D1: [Table 4-1]

[0267] [Table 4-2]

[0268] [Table 4-3]

[0269] 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-carboxylate [ka] Isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (100 mg, 0.26 mmol), N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 A mixture of 1,1'-methyl-2-nitrophenyl-1,4-diamine (70 mg, 0.26 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (51 mg, 0.08 mmol), palladium acetate (9.3 mg, 0.04 mmol), and cesium carbonate (135.3 mg, 0.4 mmol) was dissolved in dioxane (25 mL), and the reaction mixture was stirred under nitrogen gas protection at 120 °C for 2 h to complete the reaction. The reaction mixture was then filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated using a high-performance silica gel column [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-carboxylate (72 mg, yield: 43%). ESI-MS: 593.4 [M+1] + .

[0270] Intermediates E2 to E20 were produced by referring to the production method of intermediate E1: [Table 5-1]

[0271] [Table 5-2]

[0272] [Table 5-3]

[0273] [Table 5-4]

[0274] [Table 5-5]

[0275] Preparation of Intermediate E21-1: 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-carboxylate [ka] To a solution of 4-fluoro-2-methoxy-5-nitroaniline (103 mg, 0.55 mmol) in 1,4-dioxane (20 mL) was added isopropyl 2-chloro-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (200 mg, 0.55 mmol) and p-toluenesulfonic acid monohydrate (95.4 mg, 0.55 mmol). The reaction was stirred at 120 °C for 5 h. The mixture was partitioned between dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified 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-carboxylate (212 mg, yield: 73.4%). ESI-MS: 511.2 [M+1] + .

[0276] Intermediates E23-1 to E37-1 were produced by referring to the production method of intermediate E21-1: [Table 6-1]

[0277] [Table 6-2]

[0278] [Table 6-3]

[0279] Intermediate E21: Preparation of 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-carboxylate [ka] 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-carboxylate (100 mg, 0.20 mmol) in 1,4-dioxane (30 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (33.6 mg, 0.29 mmol) and diisopropylethylamine (50.6 mg, 0.40 mmol). The reaction was stirred at 120 °C for 18 h. The mixture was partitioned between dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography [dichloromethane:methanol=10:1] to give 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-carboxylate (120 mg, yield: 95%). ESI-MS: 605.3 [M+1] + .

[0280] Intermediates E22 to E77 were produced by referring to the production method of intermediate E21: [Table 7-1]

[0281] [Table 7-2]

[0282] [Table 7-3]

[0283] [Table 7-4]

[0284]

Table 7-5

[0285]

Table 7-6

[0286]

Table 7-7

[0287]

Table 7-8

[0288]

Table 7-9

[0289]

Table 7-10

[0290]

Table 7-11

[0291]

Table 7-12

[0292]

Table 7-13

[0293] Preparation of Intermediate E78: Isopropyl 4-(3,3-dimethyl-5-(propan-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-carboxylate [ka] 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-carboxylate (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 mixture was stirred at room temperature under nitrogen gas protection for 18 hours, at which point the reaction was completed. The reaction mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was purified by high-performance silica gel column chromatography [dichloromethane:methanol=10:1] to give isopropyl 4-(3,3-dimethyl-5-(propan-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-carboxylate (220 mg, yield: 79.5%). ESI-MS: 617.3 [M+1] + .

[0294] Intermediates E79 to E88 were produced by referring to the production method of intermediate E78: [Table 8-1]

[0295] [Table 8-2]

[0296] [Table 8-3]

[0297] 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-carboxylate [ka] 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-carboxylate (100 mg, 0.15 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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 mixture was stirred at 90 °C under nitrogen gas protection for 18 hours, at which point the reaction was completed. The mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was purified by high-performance 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-carboxylate (66 mg, yield: 73.3%). ESI-MS: 605.3 [M+1] + .

[0298] Intermediate E90 was prepared by referring to the preparation method of intermediate E89: [Table 9]

[0299] Preparation of Intermediate E91: 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-carboxylate [ka] 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-carboxylate (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 mixture was stirred at 90°C under nitrogen gas protection for 2 hours to complete the reaction. The reaction mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was purified by high-performance 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-carboxylate (82 mg, yield: 89.3%). ESI-MS: 604.2 [M+1] + .

[0300] Preparation of Intermediate E92: Isopropyl 4-(5-(azetidin-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-carboxylate [ka] 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-carboxylate (100 mg, 0.15 mmol), azetidine (100 mg, 1.7 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (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 mixture was stirred at 120 °C under nitrogen gas protection for 2 h, at which point the reaction was completed. The mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was purified by high-performance silica gel column chromatography [dichloromethane:methanol=10:1] to give isopropyl 4-(5-(azetidin-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-carboxylate (52 mg, yield: 53.9%). ESI-MS: 634.5 [M+1] + .

[0301] Preparation of Intermediate E93-1: 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-carboxylate [ka] 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-carboxylate (400 mg, 0.78 mmol) in 1,4-dioxane (30 mL) was added 2-(methylamino)ethan-1-ol (0.10 mL, 1.18 mmol) and diisopropylethylamine (0.26 mL, 1.57 mmol). The reaction was stirred at 120 °C for 18 h. The mixture was partitioned between dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then 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-carboxylate (120 mg, yield: 95%). ESI-MS: 566.3 [M+1] + .

[0302] Intermediates E95-1 to E97-1 and E99-1 were produced by referring to the production method of intermediate E93-1: [Table 10]

[0303] Preparation of Intermediate E93-2: Isopropyl 2-((2-methoxy-4-(methyl(2-((methylsulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate [ka] 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-carboxylate (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 removing the solvent, the residue was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to obtain isopropyl 2-((2-methoxy-4-(methyl(2-((methylsulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (470 mg, yield: 89%). ESI-MS: 644.3 [M+1] + .

[0304] Intermediates E95-2 to E97-2 and E99-2 were produced by referring to the production method of intermediate E93-2: [Table 11]

[0305] Preparation of 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-carboxylate [ka] To a solution of isopropyl 2-((2-methoxy-4-(methyl(2-((methylsulfonyl)oxy)ethyl)amino)-5-nitrophenyl)amino)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (1.0 g, 4.5 mmol) in acetonitrile (30 mL) was added pyrrolidine (0.03 mL, 0.37 mmol) and potassium carbonate (1.2 g, 9.0 mmol). The reaction was stirred at 50° C. for 18 hours. After removing the solvent, the residue was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to give 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-carboxylate (40 mg, yield: 31.7%). ESI-MS: 310.3 [M / 2+1] + .

[0306] Intermediates E94 to E100 were produced by referring to the production method of intermediate E93: [Table 12-1]

[0307] [Table 12-2]

[0308] 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-carboxylate [ka] To a 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-carboxylate (72 mg, 0.11 mmol) in methanol (20 mL) was added 10% palladium on carbon (10 mg). The reaction was stirred at room temperature for 0.5 hours, filtered, and concentrated to afford 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-carboxylate (65 mg, 86.3% yield). ESI-MS: 563.3 [M+1] + .

[0309] 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-carboxylate [ka] To a solution 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-carboxylate (129 mg, 0.21 mmol) in a 2:1 methanol / water mixture (30 mL) was added iron powder (104 mg, 1.87 mmol) and ammonium chloride (101 mg, 1.87 mmol). The reaction mixture was stirred at 100°C for 1 hour and then filtered. The resulting solution was partitioned with ethyl acetate and water, and 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-carboxylate (92 mg, yield: 74.6%). ESI-MS: 591.4 [M+1] + .

[0310] Intermediates F3 to F93 were produced by referring to the production method of intermediate F1 or F2: [Table 13-1]

[0311] [Table 13-2]

[0312] [Table 13-3]

[0313] [Table 13-4]

[0314]

Table 13-5

[0315]

Table 13-6

[0316]

Table 13-7

[0317]

Table 13-8

[0318]

Table 13-9

[0319]

Table 13-10

[0320]

Table 13-11

[0321]

Table 13-12

[0322]

Table 13-13

[0323]

Table 13-14

[0324]

Table 13-15

[0325]

Table 13-16

[0326]

Table 13-17

[0327]

Table 13-18

[0328]

Table 13-19

[0329]

Table 13-20

[0330]

Table 13-21

[0331]

Table 13-22

[0332]

Table 13-23

[0333] Preparation of Intermediate G1: Isopropyl 2-((5-acrylamido-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-carboxylate [ka] 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-carboxylate (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 mixture at 0 °C. After stirring for 30 minutes, the mixture was partitioned between 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 reverse-phase column chromatography [40-50% acetonitrile / water] to give isopropyl 2-((5-acrylamido-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-carboxylate (110 mg, yield: 64.3%). ESI-MS: 703.4 [M+1] + .

[0334] Intermediates G2 to G5 were produced by referring to the production method of intermediate G1: [Table 14]

[0335] II. Manufacture of specific embodiments Example 1: Preparation of isopropyl 2-((5-acrylamido-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-carboxylate [ka] 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-carboxylate (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 mixture at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. After concentration, the mixture was separated by reverse-phase column chromatography [40-50% acetonitrile / water] to give isopropyl 2-((5-acrylamido-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-carboxylate (7.2 mg, 11.2% yield). ESI-MS: 617.4 [M+1] + .

[0336] 1HNMR(MeOH-d4) δ 8.97 (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).

[0337] The following Examples were produced by referring to the production method of Example 1. Among them, Examples 60 to 62 were obtained by separation 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 / min.

[0338] [Table 15-1]

[0339] [Table 15-2]

[0340] [Table 15-3]

[0341] [Table 15-4]

[0342] [Table 15-5]

[0343]

Table 15-6

[0344]

Table 15-7

[0345]

Table 15-8

[0346]

Table 15-9

[0347]

Table 15-10

[0348]

Table 15-11

[0349]

Table 15-12

[0350]

Table 15-13

[0351]

Table 15-14

[0352]

Table 15-15

[0353] [Table 15-16]

[0354] [Table 15-17]

[0355] [Table 15-18]

[0356] [Table 15-19]

[0357] [Table 15-20]

[0358] [Table 15-21]

[0359] [Table 15-22]

[0360] The nuclear magnetic data of the compounds obtained by the production in the above examples are as follows: [Table 16-1]

[0361] [Table 16-2]

[0362]

Table 16-3

[0363]

Table 16-4

[0364]

Table 16-5

[0365]

Table 16-6

[0366]

Table 16-7

[0367]

Table 16-8

[0368]

Table 16-9

[0369]

Table 16-10

[0370]

Table 16-11

[0371]

Table 16-12

[0372]

Table 16-13

[0373] [Table 16-14]

[0374] [Table 16-15]

[0375] Example 9: Preparation of isopropyl 2-((5-acrylamido-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-carboxylate [ka]

[0376] First step: Synthesis of ethyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylate [ka] 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-carboxylate (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 mixture at 0 °C. The reaction was stirred at room temperature for 1 h. The mixture was partitioned with 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=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-carboxylate (660 mg, yield: 44%). ESI-MS: 423.0, 425.0 [M+1] + .

[0377] Second step: 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 [ka] Ethyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylate (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 mixture was acidified 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-carboxylate (440 mg, 71% yield). ESI-MS: 395.1, 397.1 [M+1] + .

[0378] Third step: Synthesis of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylate [ka] 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) was added N,N-dimethylformamide (0.05 mL, 0.68 mmol) and oxalyl chloride (0.20 mL, 2.28 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then isopropanol (6 mL) was added. The mixture was heated to 60°C and stirred for 1 hour. The mixture was partitioned with 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=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-carboxylate (200 mg, yield: 40%). ESI-MS: 437.0, 439.0 [M+1] + .

[0379] Fourth step: Synthesis of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylsulfonyl)pyrimidine-5-carboxylate [ka] To a solution of isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylthio)pyrimidine-5-carboxylate (200 mg, 0.46 mmol, 1 eq.) in tetrahydrofuran / water (6 mL / 0.6 mL) was added potassium hydrogen persulfate (562 mg, 0.92 mmol, 2 eq.), and the reaction was stirred at room temperature for 3 hours. The mixture was partitioned with 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-(methylsulfonyl)pyrimidine-5-carboxylate (42 mg, yield: 20%). ESI-MS: 469.1, 471.1 [M+1] + .

[0380] Fifth step: 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-carboxylate [ka] Isopropyl 4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(methylsulfonyl)pyrimidine-5-carboxylate (42 mg, 0.09 mmol, 1 eq.) and N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide (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 was stirred at room temperature for 1 hour. Water was added and stirring was continued for 0.5 hours. The mixture was partitioned with 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=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-carboxylate (46 mg, yield: 78%). ESI-MS: 657.3, 659.3 [M+1] + .

[0381] Sixth step: 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-carboxylate [ka] 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-carboxylate (46 mg, 0.07 mmol, 1 eq.), trimethylsilylacetylene (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 mixture was stirred at room temperature under nitrogen gas protection for 3 h, and then the reaction was completed. The mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, and the residue was separated by high-performance 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-carboxylate (36 mg, yield: 76.21%). ESI-MS: 675.3 [M+1] + .

[0382] Seventh step: 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-carboxylate [ka] 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-carboxylate (36 mg, 0.05 mmol, 1 eq.) in ethanol / water (3 mL / 3 mL) was added iron powder (30 mg, 0.53 mmol, 10 eq.) and ammonium chloride (29 mg, 0.53 mmol, 10 eq.). The reaction was refluxed with stirring at 95 °C for 2 h. After partitioning with dichloromethane 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-methoxyphenyl)amino)-4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidine-5-carboxylate (30 mg, yield: 73.17%). ESI-MS: 645.4 [M+1] + .

[0383] Eighth step: Synthesis of isopropyl 2-((5-acrylamido-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-carboxylate [ka] 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-carboxylate (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 mixture 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 mixture, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was partitioned with dichloromethane and water, and the organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by reverse-phase column chromatography [40-50% acetonitrile / water] to give isopropyl 2-((5-acrylamido-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-carboxylate (7.6 mg, 24% yield). ESI-MS: 627.3 [M+1] + .

[0384] 1HNMR (DMSO-d6) δ 10.08 (s, 1H), 8.83 - 8.57 (m, 3H), 7.19 (t, J = 14.6 Hz, 2H), 7.01 (s, 1H), 6.41 (dd, J = 16.9, 10.1 Hz, 1H), 6.23 (dd, J = 16.9, 2.2 Hz, 1H), 5.75 (dd, J = 10.1, 2.2 Hz, 1H), 4.93 (p, J = 6.2 Hz, 1H), 4.16 (s, 1H), 3.93 (s, 2H), 3.81 (s, 3H), 2.88 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.30 (d, J = 5.8 Hz, 2H), 2.20 (s, 6H), 1.28 (s, 6H), 1.12 (d, J = 6.2 Hz, 6H).

[0385] Example 15: Preparation of isopropyl 2-((5-acrylamido-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-carboxylate [ka] Isopropyl 2-((5-acrylamido-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-carboxylate (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 distillation under reduced pressure, and the residue was separated by reverse-phase column chromatography to give isopropyl 2-((5-acrylamido-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-carboxylate (19.1 mg, yield: 19.0%). ESI-MS: 603.4 [M+1] + .

[0386] 1 HNMR(DMSO-d6) δ 10.33 (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 (dd,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).

[0387] The following examples were produced by referring to the production method of Example 15: [Table 17]

[0388] The nuclear magnetic data of the compounds obtained by the production in the above examples are as follows: [Table 18]

[0389] Biological Measurement and Evaluation (Cell proliferation experiment) (1) Reagents and consumables Fetal bovine serum (FBS) (GBICO, Cat#10099-141), CellTiter-Glo® Luminescent Cell Vitality Detection Reagent Kit (Promega, Cat#G7572), black transparent flat-base 96-well plate (Corning®, Cat#3603).

[0390] (2) Equipment SpectraMax Multilabel Microwell Plate Detector MD, 2104-0010A, Carbon dioxide incubator, Thermo Scientific 3100 series, Biological Safety Cabinet, Thermo Scientific, 1300 Series A2, Inverted microscope, Olympus, CKX41SF, SIEMENS refrigerator KK25E76TI.

[0391] (3) Cell lines and culture conditions [Table 19]

[0392] (4) Experimental process 1. Cell culture and inoculation: (1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion to ensure that cell viability was 90% or higher. (2) The cell concentration was adjusted to the required final density, and 90 μL of the cell suspension was added to a 96-well plate. (3) In a 96-well plate, the cells were incubated overnight at 37°C, 5% CO2 and 95% humidity.

[0393] 2. T0 reference data: (1) 10 μL of PBS was added to each well of the TO plate containing the cells. (2) The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature for 30 minutes. (3) The same volume of CTG solution was added to each well. (4) The cells were shaken on an orbital shaker for 5 minutes to lyse them. (5) The cell plate was left at room temperature for 20 minutes to allow the fluorescent signal to stabilize. (6) The TO fluorescence signal value was read.

[0394] 3. Compound Dilution and Addition (1) According to the compound information table, the corresponding volume of DMSO was added to the corresponding compound powder to prepare a 10 mM stock solution. (2) Compound solutions diluted 1000-fold and 3.16-fold were prepared. (3) The 1000x diluted compound solution was diluted 100-fold with PBS to prepare 10x compound solutions, with the highest concentration being 10 μM. Nine concentrations were diluted 3.16-fold, and 10 μL of the drug solution was added to each well of a 96-well plate to inoculate the cells. Three wells were prepared for each compound concentration, and the final DMSO concentration was 0.1%. (4) The cells were placed in a 96-well plate containing the drug and subsequently cultured at 37°C, 5% CO2 and 95% humidity for 72 hours, after which CTG analysis was performed.

[0395] 4. Reading the fluorescent signal (1) The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature for 30 minutes. (2) The same volume of CTG solution was added to each well. (3) The cells were shaken on an orbital shaker for 5 minutes to lyse them. (4) The cell plate was left at room temperature for 20 minutes to allow the fluorescent signal to stabilize. (5) The fluorescence value was read.

[0396] 5. Data processing Data were analyzed with GraphPad Prism 7.0 software, and dose-effect curves were obtained by fitting the data with nonlinear S-curve regression, thereby determining IC 50 The values ​​(unit: nM) were calculated, and the specific experimental results are shown in Table 1.

[0397] Cell viability (%) = (Lum test drug - Lum medium control) / (Lum cell control - Lum medium control) x 100%.

[0398] [Table 20-1]

[0399] [Table 20-2]

[0400] According to the biological activity data of the compounds according to the specific examples, the compounds of the present invention have strong inhibitory effects on EGFR exon 20 insertions, deletions or other mutations at the cellular level, and their selectivity against EGFR WT reaches 10-fold or more, and some compounds of the examples have a selectivity of 20-fold or more. Compared with the selectivity of positive compounds, which is less than 5-fold, the compounds of the present invention have higher selectivity and have better prospects for development.

[0401] All documents pertaining to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. It should also be understood that, after reading the above disclosure of the present invention, one skilled in the art may make various variations and modifications to the present invention, and that equivalents thereof are also intended to be encompassed within the scope of the appended claims. Furthermore, the present invention includes the following aspects. [Aspect 1] Formula (I): [ka] (In the formula, X is CH or N, and Y 1 and Y 2 are each independently CH or N, and Z is CR 11 or N, R 1 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-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(=NR15 )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 R 1 and adjacent R 10 C together with the parts directly linked to them 3-12 forming a cycloalkyl group or a 3- to 12-membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-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 and optionally substituted with one or more substituents selected from the group consisting of: R 2a and R 2b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 12 、-C 0-8 Alkyl-OR 13 、-C 0-8 Alkyl-C(O)OR 13 、-C 0-8Alkyl-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 and optionally substituted with one or more substituents selected from the group consisting of: R 3a and R 3b are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups; R 4 are hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl groups, ═O, cyano groups, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of: R 5 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-4 Alkenyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R 6 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-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 selected from the group consisting of R 7 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-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 )R14 、-C 0-8 Alkyl-C(O)NR 15 R 16 and -C 0-8 Alkyl-N(R 15 )-C(O)R 14 selected from the group consisting of R 8 and R 9 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-4 Alkenyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups, or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 3-12 membered heterocyclic group, which may optionally further contain deuterium, halogen, hydroxy group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -C 0-8 Alkyl-NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of: Alternatively, R 6 、R 7 or R 9 One of the R 5 form a 4- to 6-membered heterocyclic group together with the moiety directly linked thereto, and R 6 、R 7 or R 9 and the other two of the 4-6 membered heterocyclic group are as defined above, and the 4-6 membered heterocyclic group may optionally further contain deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-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 and optionally substituted with one or more substituents selected from the group consisting of: Alternatively, R 7 and R 8 form a 4-6 membered heterocyclic group together with the moiety to which they are directly linked, and the 4-6 membered heterocyclic group may optionally further contain deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C0-8 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 and optionally substituted with one or more substituents selected from the group consisting of: or,

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Claims

1. Formula (II): 【Chemical 1】 (In the formula, Y 1 is CH or N, Z is CH or N, R 1 is hydrogen, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 cycloalkyl groups, 3- to 6-membered heterocyclic groups, and 5- to 8-membered heteroaryl groups; or R 1 and R 10 together with the moiety to which they are directly linked form a C 4-6 cycloalkyl group, which may optionally further contain halogen, C 1-4 Alkyl groups and C 3-6 optionally substituted with one or more substituents selected from the group consisting of cycloalkyl groups; R 2a and R 2b are each independently 1-4 alkyl group or R 2a and R 2b C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group, said group optionally further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 3a and R 3b are each independently selected from the group consisting of hydrogen and deuterium; R 4 is hydrogen, C 1-4 Alkyl group or C 3-6 a cycloalkyl group, said group optionally being further substituted with one or more substituents selected from the group consisting of deuterium and halogen; R 5 is hydrogen, C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R 6 is hydrogen, C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R 7 is hydrogen, C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R 8 and R 9 are each independently hydrogen, C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally be further substituted by one or more deuterium atoms; Alternatively, R 6 , R 7 or R 9 One of the and R 5 form a 4- to 6-membered heterocyclic group together with the moiety directly linked thereto, and R 6 , R 7 or R 9 the other two of which are as defined above, and said 4-6 membered heterocyclic group may optionally be further substituted by one or more halogens; Alternatively, R 7 and R 8 form a 4- to 6-membered heterocyclic group together with the moiety directly linked thereto, or, 【Chemistry 2】 has the following structure: 【Chemistry 3】 、 where R 8 is as defined above, R 10 is hydrogen or halogen, n is 0, 1, or 2) A compound represented by the formula:

2. R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl groups, or R 1 and R 10 together with the moiety to which they are directly linked form a cyclopentyl group, which is optionally further substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl; R 10 is selected from the group consisting of hydrogen, fluorine, chlorine and bromine; 2. A compound represented by formula (II) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl and cyclobutyl, and said group may be optionally further substituted with one or more substituents selected from the group consisting of deuterium and fluorine, or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1.

4. R 2a and R 2b are each independently selected from the group consisting of a methyl group, an ethyl group, and an isopropyl group, or R 2a and R 2b are, together with the carbon atom directly linked thereto, formed a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, and bromine, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1.

5. R 5 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R 6 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R 7 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R 8 and R 9 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; or R 8 and R 9 form a 4- to 6-membered heterocyclic group together with the nitrogen atom directly bonded thereto, Alternatively, R 6 , R 7 or R 9 One of the and R 5 form a 4- to 6-membered heterocyclic group together with the moiety directly linked thereto, and R 6 , R 7 or R 9 and the other two of the 4-6 membered heterocyclic group are as defined above, and the 4-6 membered heterocyclic group is optionally further substituted by one or more halogens; Alternatively, R 7 and R 8 form a 4- to 6-membered heterocyclic group together with the moiety directly linked thereto, or, 【Chemistry 4】 has the following structure: 【Chemistry 5】 、 where R 8 The compound of formula (II) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: 【Request 6】 【Chemical 6】 but has the following structure: 【Chemistry 7】 selected from the group consisting of Here, each R 5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, trideuteromethyl, and dideuteromethyl; Each R 6 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; R 7 is hydrogen, C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, Each R 8 and R 9 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trideuteromethyl, dideuteromethyl, cyclopropyl, and cyclobutyl; or R 8 and R 9 form a 4- to 6-membered heterocyclic group together with the nitrogen atom directly bonded thereto, R a is hydrogen or halogen, R b is hydrogen or halogen; 2. A compound represented by formula (II) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 【Request 7】 【Chemical 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 The compound represented by formula (II) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

8. The following steps: 【Chemistry 17】 (where Y 1 , Z, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and n is as defined in claim 1).

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

10. 10. The pharmaceutical composition of claim 9 for treating and / or preventing cancer, tumor or metastatic disease at least partly associated with an EGFR exon 20 insertion.

11. 10. The pharmaceutical composition of claim 9 for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders.

12. 10. The pharmaceutical composition of claim 9 for preventing and / or treating 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 tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma, at least in part associated with EGFR exon 20 insertion.

13. 10. The pharmaceutical composition according to claim 9 for preventing and / or treating mammary tumors.

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