2,3-Dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, their preparation and use

Abstract

The present invention relates to 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, their preparation methods, and uses. In particular, the present invention relates to EGFR inhibitors having the structure of formula (I), their preparation methods, pharmaceutical compositions containing them, and their use as EGFR inhibitors and in the treatment and / or prevention of at least some cancers, tumors, or metastatic diseases associated with EGFR exon 20 insertion or deletion mutations, particularly in the treatment of hyperproliferative diseases and cell death / damage-inducing diseases. Each substituent in formula (I) is defined as defined herein. TIFF2023545571000299.tif4157

Description

[Technical field]

[0001] The present invention relates to the field of drug synthesis, in particular to 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, their preparation methods and uses. [Background technology]

[0002] Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancers. Multi-targeted drugs targeting epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, proto-oncogene receptor tyrosine kinase (ROS1) rearrangements, and B-raf proto-oncogene, serine / threonine kinase (BRAF) have been developed and clinically validated. EGFR inhibitors have significantly improved progression-free survival in adenocarcinoma NSCLC, and after the acquisition of drug resistance mutations (first and second generation), third generation EGFR inhibitors targeting these mutations have been developed.

[0003] Despite successful inhibition of classical EGFR activating mutations (exons 19 and 21) and drug resistance mutations (T790M), in-frame insertions in exon 20 also caused constitutive activation of EGFR signaling and were associated with de novo resistance to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include in-frame insertions or duplications of amino acids 1–7 between amino acids 762–774 of the EGFR protein. In NSCLC, EGFR exon 20 mutation frequency accounts for 4–10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogenic driver mutations and are more prevalent in women, non-smokers, Asians, and adenocarcinomas in patients with non-small cell lung cancer. In addition to NSCLC, EGFR exon 20 insertion mutations have also been found in a rare form of head and neck cancer, nasal squamous cell carcinoma (SNSCC). Structurally similar exon 20 insertion mutations have also been found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.

[0004] Multiple retrospective analyses have shown that currently available first-, second-, and third-generation EGFR inhibitors have limited efficacy against exon 20 insertion mutations, except for the A763-Y764insFQEA mutation. The irreversible inhibitor poziotinib and the EGFR / MET bispecific antibody amivantamab are in clinical trials. Although several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in patients with EGFR exon 20 non-small cell lung cancer, these side effects are unavoidable due to their limited selectivity against EGFR WT (wild type), which may lead to dose-limiting toxicity. Therefore, there is an urgent need for highly selective small molecule inhibitors targeting EGFR exon 20 insertion mutations for these patients. Summary of the Invention

[0005] The object of the present invention is to provide 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, their preparation method and use. The series of compounds of the present invention have a strong inhibitory effect on the cell biological activity of EGFR exon 20 insertion, deletion or other mutations, and have high selectivity against EGFR wild type, so that they can be widely used for the preparation of medicines for treating and / or preventing cancer, tumor or metastatic diseases associated with at least some of EGFR exon 20 insertion, deletion or other mutations, especially hyperproliferative diseases and cell death / damage-induced diseases, and thus the development of a new generation of EGFR inhibitors is expected.

[0006] In a first aspect, the present invention provides a compound represented by general formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof: TIFF0007628729000001.tif4157 (wherein X and Y are each independently CR 10 or N, Z is CR 11 or N, Q is CH or N; R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 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 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido 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 groups, 5-10 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 may be substituted with one or more substituents selected from the group consisting of or, when m ≧ 1, R1 and R9 together with the moiety directly attached thereto form a C 5-6 Forming a cycloalkyl group or a 5- to 6-membered heterocyclic group, R2 and R3 are each 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; Or, R2 and R3 together with the carbon atom directly bonded to them form a C 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include 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 groups, 5-10 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 may be substituted with one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, C 1-10 Alkyl group, C 2-10 Alkenyl group, C3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl or 5-10 membered heteroaryl groups, which may optionally further comprise deuterium, halogen, hydroxyl, ═O, cyano, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be 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; 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 groups, 5-10 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)NR15 R 16 and -N(R 15 )-C(O)R 14 is selected from the group consisting of or R5 and R6 together with the moiety to which they are directly bonded form a 4-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, nitro, azide, 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 groups, 5-10 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 may be substituted with one or more substituents selected from the group consisting of R7 and R8 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-4 Alkenylene group, C 3-6 or R7 and R8 together with the moiety to which they are directly attached form a 3-12 membered heterocyclic group, which may optionally further include deuterium, halogen, hydroxyl, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10Alkyl 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 groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R9 is independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or 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 groups, 5-10 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 or when m=2, two R9 together with the moiety directly attached thereto are selected from the group consisting of C 3-12 cycloalkyl groups, 3-12 membered heterocyclic oxy groups, which may optionally further include deuterium, halogen, hydroxyl groups, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10Alkyl 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 groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 10 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or 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 groups, 5-10 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 is selected from the group consisting of R 11 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, C3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 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 may be selected from the group consisting of Each R 12 are each independently hydrogen, deuterium, a hydroxyl group, or 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, 5-10 membered heteroaryl groups and -NR 15 R 16 wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, oxo, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 13 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C6-10 aryl and 5-10 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 14 are each independently hydrogen, deuterium, a hydroxyl group, or 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 Cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 and the group is optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy groups, 5-10 membered heteroaryl groups, 5-10 membered heteroaryloxy groups and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 15 and R 16are each independently hydrogen, deuterium, a hydroxyl group, or 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 groups 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 groups and C 1-10 may be substituted with one or more substituents selected from the group consisting of alkanoyl groups; or R 15 and R 16 together with the nitrogen atom directly bonded thereto form a 4-10 membered heterocyclic or 5-10 membered heteroaryl group, which may optionally further include 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 C1-10 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 groups and C 1-10 may be substituted with one or more substituents selected from the group consisting of alkanoyl groups; m is 0, 1 or 2; Each r is independently 0, 1, or 2.

[0007] In a preferred embodiment, in the compound of formula (I), or a stereoisomer or a pharma- ceutically 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, -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 wherein the group is optionally further selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C2-4 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 or, when m≧1, R1 and R9 together with the moiety directly attached thereto may be substituted with one or more substituents selected from the group consisting of 5-6 Forming a cycloalkyl group or a 5- to 6-membered heterocyclic group, R2 and R3 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or 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 and 5-8 membered heteroaryl groups, or R2 and R3 together with the carbon atom directly bonded thereto are selected from the group consisting of C 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include 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 3-6Cycloalkyl 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 may be substituted with one or more substituents selected from the group consisting of 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 and 5-8 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl, ═O, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy 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 -NR 15 R 16 may be 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; 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 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 is selected from the group consisting of or R5 and R6 together with the moiety to which they are directly bonded form a 4-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, nitro, azide, 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 may be substituted with one or more substituents selected from the group consisting of R7 and R8 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 Alkenylene group, C 3-6 or R7 and R8 together with the moiety to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally further include 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R9 is independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or 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 or when m=2, two R9 together with the moiety directly attached thereto are selected from the group consisting of C 3-6 cycloalkyl groups, 3-6 membered heterocyclic oxy groups, which may optionally further include 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 and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 10 are each independently hydrogen, deuterium, a halogen, a cyano group, a nitro group, an azide group, or 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 , -OR13 , -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 is selected from the group consisting of R 11 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 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 is selected from the group consisting of

[0008] Here, R 12 , R 13 , R 14 , R 15 , R 16 and r are as defined for compounds of formula (I). In a preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIa): [ka] (Wherein: Z is CR 11 or N, and Q is CH or N; R1 is hydrogen, chlorine, bromine and C 1-4 alkyl groups, 1-4 The alkyl group may optionally further include deuterium, halogen, cyano, hydroxyl, amino, dimethylamino, C 3-6 may be substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R2 and R3 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include 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 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 )R14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 may be substituted with one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 cycloalkyl groups, and 3-6 membered heterocyclic 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 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R5 is hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl groups and C 2-4 alkenyl 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 selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups; R7 and R8 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4alkenyl groups, or R7 and R8 together with the moiety to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally further include 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R 9a 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 and C 6-8 aryl 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 and -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R 11is 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 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; However, R 12 , R 13 , R 14 , R 15 , R 16 and r is as described for compounds of formula (I).

[0009] In a more preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIa1): [ka] (Wherein, R2 and R3 are each independently hydrogen, deuterium, halogen, or C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl group, C 3-6 or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 3-6 cycloalkyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 may be substituted with one or more substituents selected from the group consisting of a cycloalkoxy group, a 3- to 6-membered heterocyclic group, and a 3- to 6-membered heterocyclic oxy group; R5, R7 and R8 are each independently a hydrogen atom or a methyl group; R 9a 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 and C 6-8 aryl 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 and -NR 15 R 16 and optionally substituted with one or more substituents selected from the group consisting of

[0010] In a further preferred embodiment, in the compound represented by formula (I) or its stereoisomer or pharma- ceutically acceptable salt, R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; or R2 and R3, together with the carbon atom directly bonded thereto, are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohex ... forming an xetinyl, azetidinyl, oxepentyl or azepentyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl or azepentyl group optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl and cyclobutyl; R4 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; R5, R7 and R8 are each independently a hydrogen atom or a methyl group; R 9ais selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, and phenyl, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

[0011] In a more preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIa2): [ka] wherein R4 is selected from the group consisting of isopropyl and cyclopropyl groups, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl groups.

[0012] In a more preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIa3): [ka] wherein R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, or R2 and R3 together with the carbon atom directly bonded thereto are cyclobutyl, cyclopentyl, cyclohexyl, oxetinyl, azetidinyl, oxepentyl, or azepentyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl or azepentyl group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl and cyclobutyl; R4 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; R5, R7 and R8 are each independently a hydrogen atom or a methyl group; R 9a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl and cyclobutyl; The condition is R 9aIf R2 and R3 are hydrogen, then R2 and R3 together with the carbon atom directly bonded to them form a cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl or azepentyl group.

[0013] In a more preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIa4): [ka] (Wherein: R1 is chlorine or bromine; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; or R2 and R3 together with the carbon atom directly bonded thereto are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl, or azetidinyl; pentyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl or azepentyl group being optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl and cyclobutyl; R4 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; R5, R7 and R8 are each independently a hydrogen atom or a methyl group; R 9a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, didepteromethyl, cyclopropyl, cyclobutyl, and phenyl, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, tridepteromethyl, didepteromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

[0014] In a preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIb): [ka] (Wherein, one of X and Y is CH and the other is N, and Z is CR 11 or N, Q 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, C6-8 aryl groups, 5-8 membered heteroaryl groups and -SF5, said groups optionally further comprising deuterium, halogen, cyano, nitro, azide, 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 may be substituted with one or more substituents selected from the group consisting of or R1 and R 9a C together with the moiety directly bonded to them 5-6 Forming a cycloalkyl group or a 5- to 6-membered heterocyclic group, R2 and R3 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4Alkenyl 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 may be substituted with one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 cycloalkyl groups, and 3-6 membered heterocyclic 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 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R5 is hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl groups and C 2-4alkenyl 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 selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups; or R5 and R6 together with the moiety to which they are directly bonded form a 4-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, nitro, azide, 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 may be substituted with one or more substituents selected from the group consisting of R7 and R8 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl groups and C 2-4alkenyl groups, or R7 and R8 together with the moiety to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally further include 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R 9a 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 and 5-8 membered heteroaryl groups, said groups optionally further comprising deuterium, halogen, hydroxyl, 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R11 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 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; Here, R 12 , R 13 , R 14 , R 15 , R 16 and r are as described for compounds of formula (I).

[0015] In a more preferred embodiment, the compound represented by the formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIb1) or (IIIb2): [ka] wherein one of X and Y is CH and the other is N; each Q is CH or N; Each R1 is independently hydrogen, deuterium, a halogen, a cyano group, or C 1-4 Alkyl group, C 2-4 Alkynyl group, C 3-6 cycloalkyl groups and 5-8 membered heteroaryl groups, said groups optionally further comprising 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 may be substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; or R1 and R 9a C together with the moiety directly bonded to them 5-6 Forming a cycloalkyl group or a 5- to 6-membered heterocyclic group, Each R2 and R3 is independently hydrogen, deuterium, halogen, or C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl group, C 3-6 or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, 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 may be substituted with one or more substituents selected from the group consisting of cycloalkyl groups; Each R4 is independently hydrogen, deuterium, or C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 may be substituted with one or more substituents selected from the group consisting of a cycloalkoxy group, a 3- to 6-membered heterocyclic group, and a 3- to 6-membered heterocyclic oxy group; In the compound of formula (IIIb1), R5 is hydrogen, deuterium, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl and deuterium substituted C 1-4 alkyl groups, Each R7 and R8 is independently selected from hydrogen, deuterium and C 1-4 alkyl groups, or R7 and R8 together with the nitrogen atom directly bonded thereto form a 3-6 membered heterocyclic group; Each R 9a are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups and C 6-8 aryl 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 (Optionally substituted with one or more substituents selected from the group consisting of cycloalkoxy groups, 3- to 6-membered heterocyclic groups, and 3- to 6-membered heterocyclic oxy groups)

[0016] In a more preferred embodiment, in the compound represented by the formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, each R1 is independently hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, an isopropyl group, an ethynyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, TIFF0007628729000009.tif1525 and TIFF0007628729000010.tif1429, which may optionally be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; or R1 and R 9a form a cyclopentyl group together with the moiety to which they are directly attached, Each R2 and R3 is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; or R2 and R3 together with the carbon atom directly bonded thereto form a C 3-6 A cycloalkyl group or a 3- to 6-membered heterocyclic group is formed, 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group may be further optionally substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclopropyl, and cyclobutyl; each R4 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; R5 in the compound of formula (IIIb1) is selected from the group consisting of hydrogen, deuterium and a methyl group; each R7 and R8 is independently selected from the group consisting of hydrogen, deuterium, and a methyl group; R 9aare each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, and phenyl, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl. In a preferred embodiment, the compound represented by the formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIc): [ka] (Wherein: Z is CR 11 or N, Q is CH or N, R1 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl groups, 5-8 membered heteroalkyl groups, and -SF5, 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 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 may be substituted with one or more substituents selected from the group consisting of R2 and R3 are each independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further include 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 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 16and -N(R 15 )-C(O)R 14 may be substituted with one or more substituents selected from the group consisting of R4 is hydrogen, deuterium, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 cycloalkyl groups, and 3-6 membered heterocyclic 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 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R5 is hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl groups and C 2-4 alkenyl 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 selected from the group consisting of aryl groups and 5-8 membered heteroaryl groups; or R5 and R6 together with the moiety to which they are directly bonded form a 4-6 membered heterocyclic group, which may optionally further include deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl group, C2-4 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 may be substituted with one or more substituents selected from the group consisting of R7 and R8 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 or R7 and R8 together with the nitrogen atom to which they are directly attached form a 3-6 membered heterocyclic group, which may optionally further include 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of R 11is 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 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; Here, R 12 , R 13 , R 14 , R 15 , R 16 and r is as described for compounds of formula (I).

[0017] In a more preferred embodiment, the compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (IIIc1) or (IIIc2): [ka] wherein each Q is CH or N; Each R1 is independently hydrogen, deuterium, a halogen, a cyano group, or C 1-4 and 5-8 membered heteroaryl groups, 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 may be substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; Each R2 and R3 is independently hydrogen, deuterium, halogen, or C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium substituted C 1-4 Alkyl group, C 3-6or R2 and R3, together with the carbon atom directly attached thereto, are selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 3-6 R4 independently represents hydrogen, deuterium, C 1-4 Alkyl group, C 3-6 cycloalkyl groups, which may optionally further comprise deuterium, halogen, hydroxyl groups, cyano groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 may be substituted with one or more substituents selected from the group consisting of a cycloalkoxy group, a 3- to 6-membered heterocyclic group, and a 3- to 6-membered heterocyclic oxy group; In the compound of formula (IIIc1), R5 is hydrogen, deuterium, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl and deuterium substituted C 1-4 alkyl groups, Each R7 and R8 is independently selected from hydrogen, deuterium and C 1-4 alkyl groups, or R7 and R8 together with the nitrogen atom to which they are directly bonded form a 3-6 membered heterocyclic group.

[0018] In a further preferred embodiment, in the compound represented by the formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, each R1 is independently hydrogen, deuterium, fluorine, chlorine, bromine, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, TIFF0007628729000013.tif1525 and TIFF0007628729000014.tif1529, which may optionally be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, diduteromethyl, cyclobutyl, oxycyclobutyl, and azetidinyl; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; each R4 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, which may be optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; R5 in the compound of formula (IIIc1) is selected from the group consisting of hydrogen, deuterium and a methyl group; Each R7 and R8 is independently selected from the group consisting of hydrogen, deuterium, and a methyl group. In a preferred embodiment, in the compound represented by formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, each R 12 are each independently hydrogen, deuterium, a hydroxyl group, or 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 -NR 15 R 16 wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, oxo, C1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of 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 or 5-8 membered heteroaryl groups, which may optionally further comprise deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 14 are each independently hydrogen, deuterium, a hydroxyl group, or 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 Cycloalkyloxy 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 -NR 15 R16 and wherein the group is optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy 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 -NR 15 R 16 may be substituted with one or more substituents selected from the group consisting of Each R 15 and R 16 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkoxy 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, 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 groups 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 6-8Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino groups and C 1-4 may be substituted with one or more substituents selected from the group consisting of alkanoyl groups; or R 15 and R 16 together with the nitrogen atom directly bonded thereto form a 5-8 membered heterocyclic or 5-8 membered heteroaryl group, which may optionally further include deuterium, halogen, hydroxyl, 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, di-C 1-4 Alkylamino groups and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkanoyl groups.

[0019] In the most preferred form, the compound represented by formula (I) above, or a stereoisomer or a pharma- ceutically acceptable salt thereof, includes, but is not limited to, the compounds shown below: TIFF0007628729000015.tif239142 TIFF0007628729000016.tif227133 TIFF0007628729000017.tif249141 TIFF0007628729000018.tif187146

[0020] In a second aspect of the present invention, there is provided a process for preparing a compound represented by formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof, comprising the following process steps: [ka] (wherein X1 is a halogen, preferably selected from the group consisting of fluorine, chlorine and bromine, and R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, Z, Q and m are as described for the compound of formula (I).

[0021] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) above, or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0022] The present invention also relates to the use of a compound of formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of cancer, tumor or metastatic disease associated, at least in part, with EGFR exon 20 insertions, deletions or other mutations. The present invention also relates to the use of a compound of formula (I), or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis and / or treatment of tumors, cancer, and / or metastatic disease due to disorders inducing hyperproliferation and cell death.

[0023] The present invention also relates to the use of the compound of formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating at least some EGFR exon 20 insertion, deletion or other mutation 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, breast tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urological tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma.

[0024] The present invention also relates to a compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof, which is useful as a medicament.

[0025] The present invention also relates to the use of a compound of formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof for treating and / or preventing cancer, tumor or metastatic disease associated, at least in part, with EGFR exon 20 insertions, deletions or other mutations.

[0026] The present invention also relates to the use of the compound represented by formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof for the prevention and / or treatment of tumors, cancer, and / or metastatic diseases due to disorders inducing hyperproliferation and cell death.

[0027] The present invention also relates to the use of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, breast tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcoma, paranasal sinus inverted papilloma or paranasal sinus squamous cell carcinoma associated with paranasal sinus inverted papilloma, at least in part.

[0028] The present invention also relates to a method for treating and / or preventing cancer, tumor, or metastatic disease associated, at least in part, with EGFR exon 20 insertions, deletions, or other mutations, comprising administering to a patient of interest a therapeutically effective amount of a compound represented by formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

[0029] The present invention also relates to a method for preventing and / or treating tumors, cancer, or metastatic diseases due to disorders inducing hyperproliferation and cell death, comprising administering to a patient of interest a therapeutically effective amount of a compound represented by formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

[0030] The present invention also 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, breast tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urological tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma, which comprises administering to a patient of interest a therapeutically effective amount of the compound represented by formula (I) or a stereoisomer thereof or a pharmacologic acceptable salt thereof.

[0031] Specific embodiments The inventors of the present application, after extensive and in-depth research, have developed an EGFR inhibitor having the structure of formula (I) for the first time, and the series of compounds of the present invention can be widely used for the manufacture of medicines for treating and / or preventing cancer, tumor or metastatic diseases associated with at least some of the EGFR exon 20 insertions, deletions or other mutations, particularly for the manufacture of medicines for treating hyperproliferative diseases and cell death / injury-induced diseases, and are expected to be developed as a new generation of EGFR inhibitors. Based on this, the present invention has been completed.

[0032] DETAILED DESCRIPTION: Unless expressly stated to the contrary or otherwise indicated, the following terms used in the specification and claims shall have the following meanings.

[0033] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear alkyl group and a branched alkyl group having 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, a 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-methyl ... Examples of aryl groups include, but are not limited to, ethylpentyl, 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 the various branched isomers thereof. 1-10 "Alkyl group" refers to a straight-chain alkyl group or a branched-chain alkyl group having 1 to 10 carbon atoms. 1-4 "Alkyl group" refers to straight and branched chain alkyl groups having 1 to 4 carbon atoms.

[0034] Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0035] "Cycloalkyl group" or "carbocycle" refers to a substituent of a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the partially unsaturated cyclic hydrocarbon being a ring that may contain one or more (preferably 1, 2 or 3) double bonds, but does not have a ring with a completely conjugated π-electron system. Cycloalkyl groups are divided into monocyclic cycloalkyl groups, polycyclic cycloalkyl groups, preferably cycloalkyl groups having 3 to 12, 3 to 8 or 3 to 6 carbon atoms, such as "C 3-12 "Cycloalkyl group" refers to a cycloalkyl group having a number of carbon atoms. 3-6 "Cycloalkyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms, where Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0036] Polycyclic cycloalkyl groups include spiro, fused and bridged ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share one carbon atom (called a spiro atom) between monocyclic rings, 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. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include, but are not limited to: [ka]

[0037] "Fused cycloalkyl groups" refer to all-carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of which may contain one or more (preferably one, two or three) double bonds, but no ring has a completely conjugated pi-electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic, and fused cycloalkyl groups include, but are not limited to, the following: [ka]

[0038] "Bridged cycloalkyl groups" refer to all-carbon polycyclic groups 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 no ring has a completely conjugated pi-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic or polycyclic, and bridged cycloalkyl groups include, but are not limited to, the following: [ka]

[0039] The cycloalkyl group may be fused to an aryl, heteroaryl, or heterocyclic ring, 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.

[0040] Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently 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 groups, 5-10 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 or N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0041] A "heterocyclic group" or "heterocycle" refers to a substituent of a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, which may contain one or more (preferably one, two or three) double bonds, but which does not have a ring with a completely conjugated pi-electron system, and in which one or more (preferably one, two, three or four) ring atoms are nitrogen, oxygen or S(O). r(where r is an integer of 0, 1, or 2), does not contain a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. A heterocyclic group having 3 to 12, 3 to 8, or 3 to 6 ring atoms is preferred. For example, a "3- to 6-membered heterocyclic group" refers to a ring group having 3 to 6 ring atoms, a "4- to 6-membered heterocyclic group" refers to a ring group having 4 to 6 ring atoms, a "4- to 10-membered heterocyclic group" refers to a ring group having 4 to 10 ring atoms, and a "3- to 12-membered heterocyclic group" refers to a ring group having 3 to 12 ring atoms. Monocyclic heterocyclic groups include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0042] Polycyclic heterocyclic groups include spiro, fused and bridged ring heterocyclic groups. A "spiro heterocyclic group" is a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, one or more (preferably 1, 2, 3 or 4) of which are nitrogen, oxygen or S(O) atoms. r (where r is an integer 0, 1, 2), with the remaining ring atoms being carbon. These groups may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are classified as monospiroheterocyclic groups, dispiroheterocyclic groups or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to: [ka]

[0043] 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, one or more (preferably 1, 2, 3 or 4) of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated pi-electron system and one or more (preferably 1, 2, 3 or 4) of the ring atoms are nitrogen, oxygen or S(O). r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, the fused heterocyclic group may be bicyclic, tricyclic, tetracyclic, or polycyclic, and the fused heterocyclic group may include, but is not limited to, the following: [ka]

[0044] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably 1, 2, 3, or 4) of the ring atoms are nitrogen, oxygen, or S(O). r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, the bridged heterocyclic group may be bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged heterocyclic groups include, but are not limited to, the following: [ka]

[0045] The ring of the heterocyclic group may be fused to a ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to, the following: [ka]

[0046] Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently selected from 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0047] The term "aryl group" or "aryl ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system (i.e., rings having adjacent pairs of carbon atoms), preferably an all-carbon aryl group having 5 to 10 or 5 to 8 carbon atoms, such as "C 6-10 "Aryl group" refers to an all-carbon aryl group having 6 to 10 carbon atoms, including, but not limited to, a phenyl group or a naphthyl group. 6-8 The term "aryl group" refers to an all-carbon aryl group having 6 to 8 carbon atoms. The ring of the aryl group may be fused to a heteroaryl ring, a heterocyclic ring, or a cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including, but not limited to, the following: [ka]

[0048] The aryl group may be 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 2-10 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0049] A "heteroaryl group" is a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, where the heteroatoms are nitrogen, oxygen or S(O). r(where r is an integer of 0, 1, or 2), preferably a heteroaromatic group having 5 to 10, 5 to 8, or 5 to 6 ring atoms. For example, a 5-6 membered heteroaryl group refers to a heteroaromatic group having 5 to 6 ring atoms, a 5-8 membered heteroaryl group refers to a heteroaromatic group having 5 to 8 ring atoms, and a 5-10 membered heteroaryl group refers to a heteroaromatic group having 5 to 10 ring atoms, including, but not limited to, a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, and a tetrazolyl group. The ring of the heteroaryl group may be condensed to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring connected to the parent structure is a ring of the heteroaryl group, including, but not limited to, the following: [ka]

[0050] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently 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 groups, 5-10 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 or -N(R15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0051] The term "alkenyl group" refers to an alkyl group defined above that is composed of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably an alkenyl group having 2 to 10 or 2 to 4 carbon atoms and containing a straight or branched chain, such as C 2-10 The alkenyl group is a straight-chain or branched-chain alkenyl group having 2 to 10 carbon atoms. 2-4 The alkenyl group refers to a straight-chain or branched-chain alkenyl group having 2 to 4 carbon atoms, including, but not limited to, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, and a 3-butenyl group.

[0052] The alkenyl group may be substituted or unsubstituted, and if substituted, the substituents are independently 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0053] The term "alkynyl group" refers to an alkyl group defined above that is composed of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably an alkynyl group having 2 to 10 or 2 to 4 carbon atoms and containing a straight or branched chain, such as C 2-10 The alkynyl group is a straight-chain or branched-chain alkynyl group having 2 to 10 carbon atoms. 2-4 The alkynyl group refers to a straight-chain or branched-chain alkynyl group having 2 to 4 carbon atoms, including, but not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a 3-butynyl group.

[0054] The alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are independently 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0055] The term "alkoxy group" refers to an -O-alkyl group, the alkyl group being as defined above. For example, "C 1-10 An alkoxy group having 1 to 10 carbon atoms is defined as "C 1-4 The term "alkoxy group" refers to an alkoxy group having 1 to 4 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.

[0056] The alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are independently 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0057] The term "cycloalkyloxy group" refers to -O-(cycloalkyl group), the definition of which is as above. For example, "C 3-12 A "cycloalkyloxy group" refers to a cycloalkyloxy group having 3 to 12 carbon atoms. 3-6 The term "cycloalkyloxy group" refers to a cycloalkyloxy group having 3 to 6 carbon atoms, including, but not limited to, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0058] Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0059] "Heterocycle-oxy" refers to -O-heterocycle, where heterocycle is as defined above and includes, but is not limited to, azetidinyloxy, oxetanoxy, azacyclopentyloxy, nitrogen, oxyhexyloxy, and the like.

[0060] Heterocyclic oxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are independently 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 groups, 5-10 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 or -N(R 15 )-C(O)R 14 It is preferred that the aryl group is one or more (preferably 1, 2, 3 or 4) groups selected from the group consisting of:

[0061] "C 1-10 "Alkanoyl group" means C 1-10 This refers to the monovalent atomic group remaining after removing the hydroxyl group from an alkyl acid. 0-9 For example, “C1-C(O)-” refers to an acetyl group, “C2 alkyl-C(O)-”” refers to a propionyl group, and “C3 alkyl-C(O)-” refers to a butyryl group or an isobutyryl group.

[0062] "Halogen-substituted C 1-10 The term "alkyl group" refers to an alkyl group having 1 to 10 carbon atoms in which hydrogen atoms in the alkyl group are optionally substituted with fluorine, chlorine, bromine, or iodine atoms, and includes, but is not limited to, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, and the like.

[0063] "Halogen-substituted C 1-10 The term "alkoxy group" refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogen in an alkyl group is optionally substituted with a fluorine, chlorine, bromine or iodine atom. Examples include, but are not limited to, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a tribromomethoxy group, and the like.

[0064] "Deuterium substitution C 1-10 The term "alkyl group" refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogen in the alkyl group is optionally substituted with a deuterium atom. Examples include, but are not limited to, a monodeuteromethyl group, a diduteromethyl group, a trideuteromethyl group, and the like.

[0065] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0066] "Optional" or "optionally" means that the described event or circumstance may, but does not necessarily, occur, and the statement includes cases where the event or circumstance occurs or does not occur, i.e., the two situations of substituted or 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 statement includes cases where the heterocyclic group is substituted with an alkyl group and cases where it is unsubstituted.

[0067] "Substitution" refers to the substitution of one or more "hydrogen atoms" in a group with a corresponding number of substituents, independently of each other. Of course, the substituents are in accordance with the valence bond theory in chemistry, and those in the art can easily confirm (experimentally or theoretically) whether or not the substitution is possible, provided that they are in a chemically possible position. For example, an amino group or a hydroxy group having a free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (e.g., an olefin).

[0068] The English name for "stereoisomer" is stereoisomer, which refers to an isomer resulting from differences in the arrangement of atoms in a molecule in space. They are divided into cis-trans isomers and enantiomers, and also into enantiomers and non-enantiomers. Stereoisomers resulting from the rotation of a single bond are called conformational stereoisomers, sometimes called rotamers. Stereoisomers resulting from bond length, bond angle, double bonds in a molecule, rings, etc. are called configurational stereoisomers, which are divided into two types. Isomers resulting from the inability to freely rotate the single bonds of double bonds or ring carbon atoms are called geometric isomers, also called cis-trans isomers, and are divided into Z and E configurations. For example, cis-2-butylene and trans-2-butylene are a pair of geometric isomers, and stereoisomers with different optical rotations due to the lack of antiaxial symmetry in the molecule are called optical isomers, and are divided into R and S configurations. In the present invention, unless otherwise specified, the term "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configurational isomers, and conformational isomers.

[0069] In the present invention, "pharmaceutically acceptable salts" refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0070] By "pharmaceutical composition" is meant a mixture of one or more compounds described herein, or physiologically / pharmaceutical salts or prodrugs thereof, with other chemical components, and other components, such as physiologically / pharmaceutical carriers and excipients. The purpose of a pharmaceutical composition is to exert a biological activity by facilitating administration to an organism and contributing to the absorption of the active ingredient.

[0071] The present invention will be described in more detail and completely below with reference to examples, but the present invention is not limited to the contents of the examples. Example 1

[0072] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (HNMR) 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 instrument, with deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as internal standard.

[0073] 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 pressure 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).

[0074] The silica gel plates used for thin layer chromatography are Yantai Yellow Sea HSGF254 or Qingdao GF254, with the specifications used for TLC being 0.15 mm to 0.20 mm, and the specifications used for product separation and purification by thin layer chromatography being 0.4 mm to 0.5 mm. For column chromatography, Yantai Yellow Sea silica gel with 200 to 300 mesh is usually used as the carrier.

[0075] The starting materials in the examples of the present invention are either known commercially or can be synthesized by methods known in the art.

[0076] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, under an atmosphere of dry nitrogen or argon, solvents are dry solvents, and reaction temperatures are in degrees Celsius (° C.).

[0077] 1. Manufacturing of intermediates Intermediate A1: Preparation of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0078] Step 1: Synthesis of 2-iodo-N-(2-methylallyl)pyridin-3-amine [ka] A solution of 2-iodopyridin-3-amine (5 g, 22.7 mmol) in tetrahydrofuran (100 mL) was added with a solution of potassium tert-butol in tetrahydrofuran (27 mL, 1 m, 27.2 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (3.68 g, 27.2 mmol) was slowly added dropwise to the mixture. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 2-iodo-N-(2-methylallyl)pyridin-3-amine (2.7 g, yield: 43%). ESI-MS: 275.0 [M+1] + .

[0079] Step 2: Synthesis of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 2-iodo-N-(2-methylallyl)pyridin-3-amine (2.7 g, 10 mmol), sodium formate (816 mg, 12 mmol), tetrabutylammonium chloride (3.3 g, 12 mmol), triethylamine (3 g, 30 mmol), palladium acetate (448 mg, 2 mmol), dimethylsulfoxide (50 mL) and water (3 mL). The mixture was purged with nitrogen three times and heated to 120°C under nitrogen gas protection and stirred for 1 hour. The reaction solution was filtered, the filtrate was washed with water and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure, and the crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (612 mg, yield: 41%). ESI-MS: 149.0 [M+1] + .

[0080] Preparation of Intermediate A2: 5-Chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0081] Step 1: Synthesis of 6-chloro-2-iodopyridin-3-amine [ka] N-iodobutanediimide (23.3 g, 103.5 mmol) was added to a solution of 6-chloropyridin-3-amine (12.1 g, 94.1 mmol) in N,N-dimethylformamide (200 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, and the organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 6-chloro-2-iodopyridin-3-amine (17.4 g, yield: 72.65%). ESI-MS: 254.8 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.17(d, J = 8.4 Hz, 1H), 7.03(d, J = 8.4 Hz, 1H), 5.56(s, 2H).

[0082] Step 2: Synthesis of 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine [ka] A solution of 6-chloro-2-iodopyridin-3-amine (17.4 g, 68.3 mmol) in tetrahydrofuran (200 mL), 3-bromo-2-methylpropan-1-ene (11.0 g, 82.0 mmol) and potassium tert-butol in tetrahydrofuran (82.0 mL, 1m, 82.0 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phase was combined and washed with saturated saline, and the organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine (19.4 g, yield: 91.9%). ESI-MS: 308.8 [M+1] + .

[0083] Step 3: Synthesis of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] To a solution of 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine (15.5 g, 50.2 mmol) in dimethylsulfoxide / water (200 mL / 6 mL), sodium formate (4.1 g, 60.2 mmol), tetrabutylammonium chloride (16.7 g, 60.2 mmol), triethylamine (15.2 g, 150.7 mmol) and palladium acetate (1.7 g, 7.5 mmol) were added. The reaction solution was evacuated and replaced with nitrogen, and then stirred at 120°C for 2 hours. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phase was combined and washed with saturated saline, and the organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (6.5 g, yield: 70.8%). ESI-MS: 183.1 [M+1] + .

[0084] Preparation of Intermediate A3: 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] To a solution of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (6.5 g, 35.5 mmol) in toluene (150 mL), methylboronic acid (10.7 g, 178.7 mmol), potassium phosphate (22.6 g, 106.7 mmol), tricyclic hexylphosphine (3.0 g, 10.6 mmol) and palladium acetate (1.2 g, 5.3 mmol) were added. The reaction solution was evacuated and replaced with nitrogen, and then stirred at 110°C for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, concentrated, and then separated by column chromatography [petroleum ether:ethyl acetate=3:1] to obtain 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.1 g, yield: 19.0%). ESI-MS: 163.0 [M+1] + .

[0085] Preparation of Intermediate A4: 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 three times and heated to 110° C. under nitrogen gas protection and stirred for 6 h. The reaction mixture was filtered, the filtrate was washed with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain 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] + .

[0086] Preparation of Intermediate A5: 3,3-Dimethyl-5-(1-methyl-1H-pyrazol-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-dioxaboran-2-yl)-1H-pyrazole (624 mg, 3.0 mmol), potassium phosphate (955 mg, 4.5 mmol), tricyclohexylphosphine (168 mg, 0.6 mmol), palladium acetate (67.3 mg, 0.3 mmol), and toluene (50 mL). The mixture was purged with nitrogen three times and heated to 110 °C under nitrogen gas protection and stirred for 16 h. The reaction mixture was filtered, the filtrate was washed with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (125 mg, yield: 35.7%). ESI-MS: 229.0 [M+1] + . Preparation of Intermediate A6: 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0087] Step 1: Synthesis of 6-bromo-2-iodopyridin-3-amine [ka] N-iodobutanediimide (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 at room temperature overnight. After the reaction was completed, the reaction solution was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 6-bromo-2-iodopyridin-3-amine (2.1 g, yield: 66.4%). ESI-MS: 298.8, 300.8 [M+1] + .

[0088] Step 2: Synthesis of 6-bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine [ka] Potassium tert-butol (8.4 mL, 8.4 mmol, 1 M / mL) was added to a solution of 6-bromo-2-iodopyridin-3-amine (2.09 g, 7.0 mmol) in tetrahydrofuran (50 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes. Then, 3-bromo-2-methylprop-1-ene (1.04 g, 7.7 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 6-bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine (2.1 g, yield: 69.8%). ESI-MS: 352.8, 354.8 [M+1] + .

[0089] Step 3: 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-methylallyl)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), dimethylsulfoxide (20 mL) and water (2 mL). The mixture was purged with nitrogen three times and heated to 120 °C under nitrogen gas protection and stirred for 1 h. The reaction mixture was filtered, the filtrate was washed with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain 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] + .

[0090] Intermediate A7: Preparation of 5-(1H-imidazol-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] A reaction flask was charged with 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (500 mg, 2.2 mmol), imidazole (300 mg, 4.4 mmol), potassium carbonate (913 mg, 6.6 mmol), copper iodide (83.9 mg, 0.44 mmol), (1S,2S)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (125 mg, 0.88 mmol) and dimethyl sulfoxide (8 mL) were added. The mixture was purged with nitrogen three times, and the temperature was raised to 110°C under nitrogen gas protection and stirred for 16 hours. The reaction solution was filtered, the filtrate was washed with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The crude product was separated using a flash silica gel column [eluent: methanol / dichloromethane: 0-10%] to obtain 5-(1H-imidazol-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (135 mg, yield: 26.6%). ESI-MS: 215.0 [M+1] + .

[0091] Intermediate A8: Preparation of 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0092] Step 1: Synthesis of 6-chloro-2-iodo-5-methylpyridin-3-amine [ka] N-iodobutanediimide (10.2 g, 45.6 mmol) was added to a solution of 6-chloro-5-methylpyridin-3-amine (5.0 g, 35.1 mmol) in N,N-dimethylformamide (100 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, and the organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 6-chloro-2-iodo-5-methylpyridin-3-amine (8.18 g, yield: 78.2%). ESI-MS: 269.0 [M+1] + .

[0093] Step 2: Synthesis of 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine [ka] A solution of 6-chloro-2-iodo-5-methylpyridin-3-amine (5.5 g, 20.5 mmol) in tetrahydrofuran (50 mL), 3-bromo-2-methylpropan-1-ene (3.32 g, 24.6 mmol) and potassium tert-butol in tetrahydrofuran (24.6 mL, 1 m, 24.6 mmol) were added. The reaction solution was stirred at room temperature for 20 minutes. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, and the organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine (3.55 g, yield: 53%). ESI-MS: 323.0 [M+1] + .

[0094] Step 3: Synthesis of 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] To a solution of 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine (3.35 g, 10.4 mmol) in dimethylsulfuric acid / water (60 mL / 2.6 mL), sodium formate (0.85 g, 12.5 mmol), tetrabutylammonium chloride (3.47 g, 12.5 mmol), triethylamine (31.2 g, 31.2 mmol) and palladium acetate (0.35 g, 1.5 mmol) were added. The reaction solution was evacuated and replaced with nitrogen, and then stirred at 120°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, concentrated, and then separated by column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 5-chloro-3,3,6-dimethyltri-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.5 g, yield: 67.2%). ESI-MS: 197.0 [M+1] + .

[0095] Preparation of Intermediate A9: 3,3,5,6-Tetramethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] To a solution of 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (480 mg, 2.46 mmol) in 1,2-dichloroethane (150 mL), trimethylcyclotribroxane (3.5 mL, 3.5 M, 12.3 mmol), potassium carbonate (1.02 g, 7.38 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride complex (199 mg, 0.24 mmol) were added. The reaction solution was evacuated and replaced with nitrogen, and then stirred at 120°C for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, concentrated, and then separated by column chromatography [dichloromethane:methanol=5:1] to obtain 3,3,5,6-tetramethyl-2,3-dihydro-1H-pyrrolo[3,2-b] (376 mg, yield 77.80%). ESI-MS: 177.0 [M+1] + .

[0096] Preparation of Intermediate A10: 3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka]

[0097] Step 1: Synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate [ka] 5-Bromo-2-chloro-3-nitropyridine (2.5 g, 10.53 mmol) was dissolved in acetonitrile (50 mL). Potassium 3-ethoxy-3-carbonylpropionate (2.15 g, 12.64 mmol), magnesium chloride (1.5 g, 15.79 mmol) and triethylamine (2.93 mL, 21.06 mmol) were added. The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was adjusted to pH=7 with 1N hydrochloric acid, extracted with dichloromethane (100 mL), and the organic phase was washed with water (50 mL) and saturated saline (50 mL) in that order. The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether:ethyl acetate=3:1] to give ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (890 mg, yield: 29%). ESI-MS: 289.0, 290.9 [M+1] + .

[0098] Step 2: Synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropionate [ka] Ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (710 mg, 2.46 mmol) was dissolved in tetrahydrofuran (50 mL), and 18-crown ether-6 (64.9 mg, 0.25 mmol), iodomethane (0.46 mL, 7.37 mmol) and sodium hydride (177 mg, 7.37 mmol) were added to the reaction solution. The reaction solution was stirred at 0°C for 3 hours under nitrogen gas protection, and after the reaction was completed, the reaction solution was separated by adding ethyl acetate (100 mL) and saturated saline (100 mL), and the organic phase was washed with saturated saline (50 mL). The obtained organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate = 3 / 1] to obtain ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate (532 mg, yield: 68%). ESI-MS: 317.0, 319.0 [M+1] + .

[0099] Step 3: Synthesis of 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] Ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropionate (532 mg, 1.68 mmol) and iron powder (940 mg, 16.77 mmol) were dissolved in glacial acetic acid (10 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting residue was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL). The organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate=2 / 1] to obtain 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (270 mg, yield: 66%). ESI-MS: 241.0, 243.0 [M+1] + .

[0100] Step 4: Synthesis of 3,3,6-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] 6-Bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (140 mg, 0.58 mmol), trimethylboroxyhexane (108 mg, 0.87 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (42 mg, 0.058 mmol) and potassium carbonate (161 mg, 1.16 mmol) were dissolved in dimethoxyethylene glycol (5 mL), and the reaction solution was stirred at 90°C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=2 / 1] to give 3,3,6-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (85 mg, yield: 83%). ESI-MS: 177.0 [M+1] + .

[0101] Step 5: Synthesis of 3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 3,3,6-Trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (85 mg, 0.48 mmol) was dissolved in tetrahydrofuran (20 mL), and borane tetrahydrofuran solution (1.4 mL, 1.4 mmol) was added to the reaction solution. The reaction solution was stirred at 70°C for 16 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The obtained organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate = 2 / 1] to obtain 3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (63 mg, yield: 80%). ESI-MS: 163.0 [M+1] + .

[0102] Intermediates A11 and A12 were obtained by producing them with reference to the synthetic method of intermediate A10. TIFF0007628729000055.tif89160

[0103] Preparation of Intermediate A13: 5'-Methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0104] Step 1: Synthesis of diethyl-2-(6-methyl-3-nitropyridin-2-yl)malonate [ka] Diethyl malonate (11.14 g, 69.54 mmol) was slowly added dropwise to a suspension of sodium hydride (3.01 g, 75.33 mmol) in dimethyl sulfoxide (140 mL) at 0°C. The mixture was stirred at room temperature for 0.5 hours, and then 2-chloro-6-methyl-3-nitropyridine (10 g, 57.95 mmol) was added to the mixture. The reaction solution was stirred at 100°C for 1.5 hours, and after the reaction was completed, it was cooled to 0°C and quenched by slowly adding saturated sodium bicarbonate. The mixture was washed with 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 flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to obtain diethyl-2-(6-methyl-3-nitropyridin-2-yl)malonate (8.66 g, yield: 45.9%). ESI-MS: 297.1 [M+1] + .

[0105] Step 2: Synthesis of ethyl-2-(6-methyl-3-nitropyridin-2-yl)acetate [ka] To a solution of diethyl-2-(6-methyl-3-nitropyridin-2-yl)malonate (8.66 g, 26.60 mmol) in dimethylsulfoxide (65 mL), water (10 mL) and lithium chloride (2.74 mL, 132.99 mmol) were added. The mixture was stirred at 100°C for 4 days. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-50%] to obtain ethyl-2-(6-methyl-3-nitropyridin-2-yl)acetate (2.1 g, yield: 33.45%). ESI-MS: 225.0 [M+1] + .

[0106] Step 3: Synthesis of ethyl-1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate [ka] Diphenyl(vinyl)sulfonium trifluoromethanesulfonate (565 mg, 1.56 mmol) was added to a solution of ethyl-2-(6-methyl-3-nitropyridin-2-yl)acetate (180 mg, 0.80 mmol) in dimethylsulfoxide (10 mL) under nitrogen gas protection at room temperature, and the mixture was stirred at room temperature for 10 minutes, followed by the addition of dried 1,8-diazabicycloundecane-7-ene (DBU) (0.36 mL, 2.41 mmol). After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-25%] to obtain ethyl-1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate (144 mg, yield: 68.09%). ESI-MS: 251.2 [M+1] + .

[0107] Step 4: Synthesis of 5'-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one [ka] To a solution of ethyl-1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate (144 mg, 0.55 mmol) in ethanol (20 mL), ammonium formate (0.14 mL, 2.73 mmol) and 10% palladium on carbon (20 mg) were added, and the mixture was stirred at 90°C for 18 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain the crude product of 5'-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (80 mg, yield: 77.29%), which was used directly in the next reaction step. ESI-MS: 175.0 [M+1] + .

[0108] Step 5: 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 (80 mg, 0.42 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C. A solution of lithium tetrahydroaluminum in tetrahydrofuran (0.83 mL, 2.07 mmol) was added dropwise to the solution. The mixture was stirred at 50°C for 3 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain 5'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (64 mg, yield: 78.28%). ESI-MS: 161.0 [M+1] + .

[0109] Preparation of Intermediate A14: 5'-Methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0110] Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate [ka] 1-tert-Butyl 3-ethylmalonate (35.45 g, 188.3 mmol) was slowly added dropwise to a suspension of sodium hydride (6.95 g, 173.8 mmol) in tetrahydrofuran (200 mL) at 0°C. The mixture was stirred in an ice bath for 0.5 hours, and then 2-chloro-6-methyl-3-nitropyridine (25 g, 144.8 mmol) was added to the mixture. The reaction solution was stirred at 60°C for 18 hours, and after the reaction was completed, it was cooled to 0°C and ice water was slowly added to quench the reaction. The mixture was washed with 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 on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-20%] to obtain 1-(tert-butyl) 3-ethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate (41 g, yield: 73.3%). ESI-MS: 325.0 [M+1] + .

[0111] Step 2: 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, distilled under reduced pressure, and the crude product was separated on a flash silica gel column [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] + .

[0112] Step 3: 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 under a hydrogen atmosphere, and after the reaction was completed, it was filtered and distilled under reduced pressure to obtain ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate (17.5 g, yield: 82%). ESI-MS: 195.0 [M+1] + .

[0113] Step 4: 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 (1M) (100 mL), and the mixture was stirred at 55° C. for 5 hours. After the reaction was completed, the mixture was adjusted to basicity with saturated sodium bicarbonate and extracted several times with dichloromethane:methanol=10:1 solvent. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated using a flash silica gel column [eluent: dichloromethane / methanol: 0-10%] to obtain 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (7.8 g, yield: 67%). ESI-MS: 149.0 [M+1] + .

[0114] Step 5: 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 hexamethylphosphatidyltriamine (2 mL), 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 to the solution. The mixture was stirred at 0°C for 1 hour. After completion of the reaction, the reaction solution 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 on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to obtain 5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (260 mg, yield: 20%). ESI-MS: 189.0 [M+1] + .

[0115] Step 6: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine [ka] 5'-Methanespiro[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 tetrahydroaluminum in tetrahydrofuran (1.7 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] (260 mg, yield: 76%). ESI-MS: 175.0 [M+1] + .

[0116] Preparation of Intermediate A15: 5'-Methyl-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0117] Step 1: Synthesis of 5'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one [ka] 5-Methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (800 mg, 5.4 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and hexamethylphosphoryltriamine (4.7 mL), cooled to -78°C, and n-butyllithium (6.5 mL, 16.2 mmol) in tetrahydrofuran was slowly added dropwise to the solution. The reaction solution was stirred for 30 minutes, and 1,4-diiodobutane (1.4 mL, 9.5 mmol) was added dropwise. The mixture was stirred at -20°C for 1 hour. After completion of the reaction, the reaction solution 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 on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to obtain 5'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (450 mg, yield: 41%). ESI-MS: 203.0 [M+1] + .

[0118] Step 2: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine] [ka] 5'-Methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (545 mg, 2.7 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. A solution of lithium tetrahydroaluminum in tetrahydrofuran (1.7 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] (465 mg, yield: 83%). ESI-MS: 189.0 [M+1] + .

[0119] Preparation of Intermediate A16: 5'-Methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0120] Step 1: Synthesis of 5'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one [ka] 5-Methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (200 mg, 1.35 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and hexamethylphosphoryltriamine (1.5 mL), cooled to -78°C, and n-butyllithium (1.89 mL, 4.73 mmol) in tetrahydrofuran was slowly added dropwise to the solution. The reaction solution was stirred for 30 minutes, and 1,5-diiodopentane (0.60 mL, 4.05 mmol) was added dropwise. The mixture was stirred at -20°C for 1 hour. After completion of the reaction, the reaction solution 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 on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to give 5'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (220 mg, yield: 75.36%). ESI-MS: 217.0 [M+1] + .

[0121] Step 2: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine] [ka] 5'-Methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (220 mg, 1.01 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C. A solution of lithium tetrahydroaluminum in tetrahydrofuran (1.02 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 5'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine] (190 mg, yield: 92.2%). ESI-MS: 203.0 [M+1] + .

[0122] Preparation of Intermediate A17: 5'-Methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyrano-4,3'-pyrrolo[3,2-b]pyridine] [ka]

[0123] Step 1: Synthesis of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyrano-4,3'-pyrrolo[3,2-b]pyridin]-2'-one [ka] 5-Methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (450 mg, 3.04 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and hexamethylphosphoryltriamine (5 mL), cooled to -78°C, and n-butyllithium (3.65 mL, 9.11 mmol) in tetrahydrofuran was slowly added dropwise to the solution. The reaction mixture was stirred for 30 minutes, and 1-iodo-2-(2-iodoethoxy)ethane (1.980 g, 6.08 mmol) was added dropwise. The mixture was stirred at -20°C for 1 hour. After 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 on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to obtain 5'-methyl-2,3,5,6-tetrahydro-2'H-1'-12 spiro[pyrano-4,3'-pyrrolo[3,2-b]pyridin]-2'-one (191 mg, yield: 28.81%). ESI-MS: 219.3 [M+1] + .

[0124] Step 2: Synthesis of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyrano-4,3'-pyrrolo[3,2-b]pyridine] [ka] 5'-Methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyrro-4,3'-pyrrolo[3,2-b]pyridin]-2'-one (191 mg, 0.88 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to 0°C. A solution of lithium tetrahydroaluminum in tetrahydrofuran (0.88 mL, 2.5M) was added dropwise to the solution. The mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyrano-4,3'-pyrrolo[3,2-b]pyridine] (175 mg, yield: 97.9%). ESI-MS: 205.2 [M+1] + .

[0125] Intermediate A18: Preparation of 1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0126] Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl)malonate [ka] 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) at 0°C. The mixture was stirred at room temperature for 0.5 hours, and then 2-chloro-3-nitropyridine (25.0 g, 157.7 mmol) was added to the mixture. The reaction solution was stirred at 60°C for 1.5 hours, and after the reaction was completed, it was cooled to 0°C and quenched by slowly adding saturated aqueous ammonium chloride solution. The mixture was washed with 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 on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-50%] to obtain 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl) malonate (32.7 g, yield: 66.8%). ESI-MS: 255.0 [M-55] + .

[0127] Step 2: 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 solution was cooled to room temperature, and then distilled under reduced pressure to remove trifluoroacetic acid. The residue was added to a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain ethyl 2-(3-nitropyridin-2-yl)acetate (17.7 g, yield: 91.9%). ESI-MS: 211.0 [M+1] + .

[0128] Step 3: Synthesis of ethyl 2-(3-aminopyridin-2-yl)acetate [ka] To a solution of ethyl 2-(3-nitropyridin-2-yl)acetate (22 g, 104.7 mmol) in methanol (150 mL) was added 10% palladium on carbon (3.0 g). The mixture was stirred overnight at room temperature under a hydrogen atmosphere, and after the reaction was completed, it was filtered and distilled under reduced pressure to obtain ethyl 2-(3-aminopyridin-2-yl)acetate (17.5 g, yield: 90%). ESI-MS: 181.0 [M+1] + .

[0129] Step 4: Synthesis of 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one [ka] Ethyl 2-(3-aminopyridin-2-yl)acetate (17.5 g, 96.6 mmol) was added to a solution of hydrochloric acid (1M) (100 mL), and the mixture was stirred at 55°C for 5 hours. After the reaction was completed, the mixture was adjusted to basicity with saturated sodium bicarbonate and extracted several times with dichloromethane:methanol = 10:1 solvent. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated using a flash silica gel column [eluent: dichloromethane / methanol: 0-10%] to obtain 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (7.8 g, yield: 60%). ESI-MS: 135.0 [M+1] + .

[0130] Step 5: 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 hexamethylphosphatidyltriamine (12 mL) were dissolved in anhydrous N,N-dimethylformamide (60 mL), and 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4.0 g, 29.8 mmol) and 1,3-diiodopropane (8.8 g, 29.8 mmol) were added to the reaction solution. The reaction solution was stirred at 0°C for 1 hour under nitrogen gas protection, and after the reaction was completed, the reaction solution was separated by adding ethyl acetate (100 mL) and saturated saline (100 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=3:1] to give spiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (1.2 g, yield: 23%). ESI-MS: 175.0 [M+1] + .

[0131] Step 6: 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), and borane tetrahydrofuran solution (1.4 mL, 1.4 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 16 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The obtained organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate = 2:1] to obtain 1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] (210 mg, yield: 95%). ESI-MS: 161.0 [M+1] + .

[0132] Preparation of Intermediate A19: 3,3-Difluoro-5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] [ka]

[0133] Step 1: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide [ka] 2-Bromo-6-methylpyridin-3-amine (5 g, 26.732 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (4.37 g, 32.079 mmol), 1-methylimidazole (6.58 g, 80.197 mmol) were dissolved in acetonitrile (150 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (9.00 g, 32.078 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution 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 on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to obtain N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide (7.8 g, yield: 95%). ESI-MS: 304.8 [M+1] + .

[0134] Step 2: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide [ka] To a solution of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide (3.0 g, 9.8 mmol) in acetonitrile (50 mL), 1-(chloromethyl)-4-methoxybenzene (2.01 mL, 14.75 mmol) and potassium carbonate (4.08 g, 29.50 mmol) were added. The mixture was stirred at 90°C for 18 hours, and after the reaction was completed, it was filtered and distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-25%] to obtain N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide (3.8 g, yield: 90%). ESI-MS: 425.0 [M+1] + .

[0135] Step 3: 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-carboxamide (3.2 g, 7.5 mmol) in dioxane (50 mL), [1,3-bis(2,6-diisopropylbenzene)imidazole-2-folk](3-chloropyridine)dichloride palladium (512 mg, 0.7 mmol) and tert-butanol sodium (1.45 g, 15.0 mmol) were added, and the mixture was stirred at 100°C for 5 hours under nitrogen gas protection. After 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, distilled under reduced pressure, and the crude product was separated on a flash silica gel column [eluent: petroleum ether / ethyl acetate: 0-30%] to obtain 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1H)one (2.0 g, yield: 77%). ESI-MS: 345.0 [M+1] + .

[0136] Step 4: 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. After the reaction was completed, the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-50%] to obtain 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] + .

[0137] Step 5: 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), cooled to 0°C, and a solution of lithium tetrahydroaluminum in tetrahydrofuran (1.3 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 3,3-difluoro-5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] (250 mg, yield: 100%). ESI-MS: 211.0 [M+1] + .

[0138] Preparation of Intermediate A20: tert-Butyl 5'-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka]

[0139] Step 1: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)azetidine-1-carboxylate [ka] 2-Bromo-6-methylpyridin-3-amine (3.5 g, 18.7 mmol), 1-(t-butoxycarbonyl)acridinium-3-carboxylate (4.52 g, 22.5 mmol), and N-methylimidazole (6.45 g, 78.6 mmol) were dissolved in acetonitrile (55 mL). N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (7.35 g, 26.42 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (100 mL), and the organic phase was washed with water (50 mL) and saturated saline (50 mL) in that order. The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether:ethyl acetate=1:1] to give the crude product of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)azetidine-1-carboxylate (10.2 g, yield: 147%). ESI-MS: 370.0, 372.0 [M+1] + .

[0140] Step 2: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate [ka] tert-Butyl 3-((2-bromo-6-methylpyridin-3-yl)carbacolin)acridinium-1-carboxylate (10.2 g, 22.03 mmol) was dissolved in acetonitrile (1800 mL), and p-methoxybenzyl chloride (9.0 mL, 66.0 mmol) and potassium carbonate (5.5 g, 39.8 mmol) were added to the reaction solution. The reaction solution was stirred at 110 °C for 4 hours under nitrogen gas protection, and after the reaction was completed, the reaction solution was separated by adding ethyl acetate (100 mL) and saturated saline (100 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=2 / 1] to give tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (3.5 g, yield: 32.4%). ESI-MS: 434.0, 436.0 [M+1] + .

[0141] Step 3: Synthesis of tert-butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate (3.5 g, 7.1 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (PEPPSI-iPr) (240 mg, 0.36 mmol), and sodium tert-butanol (1.03 g, 10.7 mmol) were dissolved in 1,4-dioxane (60 mL). The reaction solution was stirred for 18 hours under heating at 110°C using a microwave. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting residue was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=3 / 1] to give tert-butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (640 mg, yield: 21.9%). ESI-MS: 410.2 [M+1] + .

[0142] Step 4: Synthesis of tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (640 mg, 1.56 mmol) was dissolved in dichloromethane (2 mL), trifluoromethanesulfonic acid (3 mL) was added, and the reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was separated by the addition of ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=1 / 1] to give tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (370 mg, yield: 81.82%). ESI-MS: 234.0 [M+1] + .

[0143] Step 5: Synthesis of tert-butyl 5'-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (370 mg, 1.28 mmol) was dissolved in tetrahydrofuran (6 mL), and borane tetrahydrofuran solution (6.4 mL, 12.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The obtained organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate = 1 / 1] to obtain tert-butyl 5'-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (264 mg, yield: 75.0%). ESI-MS: 276.0 [M+1]+ .

[0144] Preparation of Intermediate A21: tert-Butyl 5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka]

[0145] Step 1: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate [ka] 2-Bromo-6-methylpyridin-3-amine (3.0 g, 16.0 mmol), 1-(tert-butoxycarbonyl)-pyrrolidine-3-carboxylic acid (3.45 g, 16.0 mmol), and N-methylimidazole (5.370 mL, 67.4 mmol) were dissolved in acetonitrile (100 mL). N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (6.3 g, 22.4 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (100 mL), and the organic phase was washed with water (50 mL) and saturated saline (50 mL) in that order. The organic phase was concentrated, and the residue was separated by flash silica gel column [petroleum ether:ethyl acetate=1:1] to give tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (5.1 g, yield: 83%). ESI-MS: 384.3, 386.3 [M+1] + .

[0146] Step 2: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate [ka] tert-Butyl 3-((2-bromo6-methylpyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (5.1 g, 13.3 mmol) was dissolved in acetonitrile (50 mL), and p-methoxybenzyl chloride (2.7 mL, 20.0 mmol) and potassium carbonate (5.5 g, 39.8 mmol) were added to the reaction solution. The reaction solution was stirred at 90 °C for 18 hours under nitrogen gas protection, and after the reaction was completed, the reaction solution was separated by adding ethyl acetate (100 mL) and saturated saline (100 mL), and the organic phase was washed with saturated saline (50 mL). The obtained organic phase was concentrated, and the residue was separated using a flash silica gel column [petroleum ether / ethyl acetate = 2 / 1] to obtain tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate (3.5 g, yield: 53%). ESI-MS: 448.2, 450.2 [M+1] + .

[0147] Step 3: Synthesis of tert-butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate (600 mg, 1.19 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (PEPPSI-iPr) (136.20 mg, 0.2 mmol), and sodium tert-butanol (343 mg, 3.57 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was stirred for 5 hours under heating at 110° C. using a microwave. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting residue was separated by adding ethyl acetate (50 mL) and saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=3 / 1] to give tert-butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (350 mg, yield: 69%). ESI-MS: 424.2 [M+1] + .

[0148] Step 4: Synthesis of tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 1'-(4-methoxybenzyl)-5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (350 mg, 0.83 mmol) was dissolved in dichloromethane (10 mL), trifluoromethanesulfonic acid (0.74 mL, 8.3 mmol) was added, and the reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was separated by the addition of ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=1 / 1] to give tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (220 mg, yield: 88%). ESI-MS: 304.0 [M+1] + .

[0149] Step 5: Synthesis of tert-butyl 5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate [ka] tert-Butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (220 mg, 0.73 mmol) was dissolved in tetrahydrofuran (10 mL), and a borane tetrahydrofuran solution (7.2 mL, 7.2 mmol) was added to the reaction solution. The reaction solution was stirred at 70°C for 16 days under nitrogen gas protection. After the reaction was completed, the reaction solution was separated by the addition of ethyl acetate (50 mL) and saturated saline (50 mL), and the organic phase was washed with saturated saline (50 mL). The organic phase was concentrated, and the residue was separated on a flash silica gel column [petroleum ether / ethyl acetate=1 / 1] to give tert-butyl 5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (200 mg, yield: 95%). ESI-MS: 290.2 [M+1] + .

[0150] Preparation of Intermediate A22: 3,3-Dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine [ka]

[0151] Step 1: Synthesis of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one [ka] Nitric acid (65% mass fraction, 5.4 g, 55.6 mmol) was slowly added dropwise to concentrated sulfuric acid (98% mass fraction, 30 mL) of 1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (450 mg, 2.5 mmol) at 0°C, the mixture was stirred at 0°C for 1 hour, slowly poured into ice water, stirred for 1 hour, filtered, and the filter cake was dried to obtain 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (3.5 g, yield: 52.5%). ESI-MS: 181.0 [M+1] + .

[0152] Step 2: Synthesis of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine [ka] To a solution of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (2.5 g, 13.9 mmol) in acetonitrile (50 mL), trichloroxaphos (6.4 g, 41.6 mmol) and triethylbenzylammonium chloride (1.9 g, 7.0 mmol) were added, and the mixture was stirred at 80°C for 1 h, concentrated under reduced pressure to remove the solvent, and the residue was slowly poured into ice water and stirred for 30 min. Extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-50%] to give 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (985 mg, yield: 36.0%). ESI-MS: 198.9 [M+1] + .

[0153] Step 3: Synthesis of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)malonate [ka] Sodium hydride (220 mg, 5.5 mmol) was added to a solution of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (814 mg, 5.1 mmol) in dimethyl sulfoxide (10 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 hours, diethyl malonate (840 mg, 4.2 mmol) was added to the mixture, the reaction was stirred at 100° C. for 1 hour, cooled to room temperature, and the reaction was quenched with saturated aqueous ammonium chloride solution, the reaction solution was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)diethyl malonate (409 mg, yield: 30.0%). ESI-MS: 323.0 [M+1] + .

[0154] Step 4: Synthesis of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)acetate [ka] To a solution of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl))malonate (409 mg, 1.3 mmol) in dimethylsulfoxide (5 mL), water (0.91 mL, 5.1 mmol) and lithium chloride (267 mg, 6.4 mmol) were added. The mixture was stirred at 100°C for 24 hours. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-50%] to obtain ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)acetate (240 mg, yield: 76.0%). ESI-MS: 251.0 [M+1] + .

[0155] Step 5: Synthesis of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)propionate [ka] At 0°C, iodomethane (300 mg, 2.1 mmol), 18-crown-6 (26 mg, 0.1 mmol) were added to a solution of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)acetate (240 mg, 0.96 mmol) in N,N-dimethylformamide (5 mL), followed by slow addition of sodium hydride (88 mg, 2.2 mmol). The mixture was stirred at 0°C for 1 hour, and after completion of the reaction, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was separated using a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-25%] to obtain ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)propionate (150 mg, yield: 56.0%). ESI-MS: 279.0 [M+1] + .

[0156] Step 6: Synthesis of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopenta[b]pyrrolo[2,3-e]pyridin-2(1H)-one [ka] To a solution of 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)propionic acid (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. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain the crude product of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopenta[b]pyrrolo[2,3-e]pyridin-2(1H)-one, which was used directly in the next reaction step. ESI-MS: 203.0 [M+1] + .

[0157] Step 7: Synthesis of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine [ka] The crude product of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopenta[b]pyrrolo[2,3-e]pyridin-2(1H)-one was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C. A solution of lithium tetrahydroaluminum in tetrahydrofuran (2 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were observed. The mixture was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine. ESI-MS: 189.0 [M+1] + .

[0158] Intermediate B1: Preparation of 1-(2-chloropyridin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 3,3-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (550 mg, 3.71 mmol) and 2-chloro-4-fluoropyridine (730 mg, 5.57 mmol) were dissolved in 10 mL N,N-dimethylformamide. A solution of potassium tert-butoxide in tetrahydrofuran (5.6 mL, 1m, 5.57 mmol) was added to the solution at room temperature. The reaction solution was stirred at 100°C for 1 hour. Water was added to the solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated saline, and then dried over anhydrous sodium sulfate. After removing the solvent, the mixture was separated by silica gel column chromatography [petroleum ether:ethyl acetate=5:1] to obtain 1-(2-chloropyridin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (480 mg, yield: 60%). ESI-MS: 260.0 [M+1] + .

[0159] Intermediates B2 and B3 were obtained by producing them with reference to the synthesis method of intermediate B1. TIFF0007628729000112.tif90160

[0160] Intermediate B4: Preparation of 1-(2-chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 2,4-Dichloropyrimidine (827 mg, 5.6 mmol), 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (600 mg, 3.7 mol), N,N-diisopropylethylamine (1.43 g, 11.1 mmol) and isopropanol (15 mL) were added to a microwave tube in this order. The reaction solution was heated at 100°C using a microwave for 18 hours. After completion of the reaction, the solvent was removed and the crude product was separated by column chromatography [ethyl acetate / petroleum ether: 0-30%] to obtain 1-(2-chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (520 mg, yield: 50%). ESI-MS: 275.0 [M+1] + .

[0161] Intermediates B5-B19 were obtained by producing them with reference to the synthetic method of intermediate B4. TIFF0007628729000114.tif204153 TIFF0007628729000115.tif199153 TIFF0007628729000116.tif206152

[0162] Intermediate B20: Preparation of 1-(4-chloro-1,3,5-triazin-2-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] At room temperature, 2,4-dichloro-1,3,5-triazine (377 mg, 2.51 mmol) was dissolved in dichloromethane (10 mL) and N,N-diisopropylethylamine (542 mg, 4.19 mmol) was added. While stirring, a solution of 3,3-dimethyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (340 mg, 2.1 mmol) in dichloromethane (10 mL) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed and the product was separated by silica gel column chromatography [petroleum ether:ethyl acetate=4:1] to obtain 1-(4-chloro-1,3,5-triazin-2-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (300 mg, yield: 52%). ESI-MS: 276.1 [M+1] + .

[0163] Intermediate B21 was obtained by producing with reference to the synthetic method of intermediate B20. TIFF0007628729000118.tif52153

[0164] Preparation of Intermediate B22: 1-(6-chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 4,6-Dichloropyrimidine (347 mg, 1.84 mmol) was dissolved in 15 mL of isopropanol. 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (250 mg, 1.53 mmol) and N,N-diisopropylethylamine (395 mg, 3.06 mmol) were added to the solution at room temperature. The reaction solution was heated to 80°C and stirred for 16 hours. After the reaction was completed, the solvent was removed and the product was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to obtain 1-(6-chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (266 mg, yield: 63%). ESI-MS: 275.0 [M+1] + .

[0165] Intermediates B23-B25 were produced with reference to the synthetic method of intermediate B22. TIFF0007628729000120.tif113153

[0166] Intermediate B26: Preparation of 1-(2-chloropyrimidin-4-yl)-3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 3,3-Dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.44 mmol) was dissolved in 8 mL of N,N-dimethylformamide, and the solution was cooled to 0°C. Sodium hydrogen (70 mg, 1.75 mmol) was added to the solution, and the mixture was stirred for 0.5 hours. After that, 2,4-dichloropyrimidine (261 mg, 1.75 mmol) was added. The mixture was added with 1,2,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, yield: 64.4%). ESI-MS: 341.0 [M+1] + .

[0167] Intermediates B27 and B28 were produced with reference to the synthetic method of intermediate B26. TIFF0007628729000122.tif96150

[0168] Preparation of Intermediate B29: 5-Bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0169] Step 1: Synthesis of 5-bromo-3,3-dimethyl-1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (800 mg, 3.52 mmol) was dissolved in 8 mL of N,N-dimethylformamide and cooled to 0 ° C., sodium hydrogen carbonate (563.6 mg, 14 mmol) was added to the solution, and the mixture was stirred for 0.5 hours. Then, 4-chloro-2-(methylthio)pyrimidine (1.13 g, 7.0 mmol) was added to the mixture, and the reaction solution was stirred at 0 ° C. for 18 hours, cooled to room temperature, and the reaction was quenched with a small amount of water, washed with water, extracted with ethyl acetate, dried, the solvent was removed, and the residue was subjected to column chromatography to obtain the product 5-bromo-3,3-dimethyl-1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (941 mg, yield: 60.8%). ESI-MS: 351.0, 353.0 [M+1] + .

[0170] Step 2: Synthesis of 5-bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine [ka] 5-Bromo-3,3-dimethyl-1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (941 mg, 2.68 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL), methanol (10 mL) and water (3 mL), and potassium persulfate (3.29 g, 5.36 mmol) was added. The reaction solution was stirred at room temperature overnight, filtered, the filtrate was washed with water, extracted with ethyl acetate, dried, and distilled under reduced pressure to remove the organic solvent, and the residue was subjected to column chromatography to obtain 5-bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (642 mg, yield: 59.4%). ESI-MS: 383.0, 385.0 [M+1] + .

[0171] Intermediate C1:N1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitrobenzene-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 1,2-Trimethylolethane-1,2-diamine (1.53 g, 15.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added. The reaction solution was stirred at 85°C for 3 hours. Water was added to this solution, and it was extracted three times with dichloromethane. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After removing the solvent, it was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] and purified by N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitrobenzene-1,4-diamine (2.5 g, yield: 93%) was obtained. ESI-MS: 269.0 [M+1] + .

[0172] Intermediate C2 was obtained by producing with reference to the synthetic method of intermediate C1. TIFF0007628729000126.tif53160

[0173] Intermediate C3: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 -Methyl-2-nitrobenzene-1,4-diamine [ka]

[0174] Step 1: Synthesis of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene [ka] 5-Fluoro-2-nitrophenol (10.00 g, 63.65 mmol) and sodium carbonate (20.24 g, 190.96 mmol) were dissolved in N,N-dimethylformamide (100 mL), and 2-chloro-2,2-difluoroacetic acid sodium salt (33.97 g, 222.79 mmol) was added in portions at 90°C. The reaction mixture was stirred at this temperature for 3 h and monitored by TLC. The reaction mixture was cooled to room temperature, poured into ice water, and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [eluent: ethyl acetate / petroleum ether: 0-10%] to obtain 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, 49.57 mmol, yield: 77.88%). 1 H NMR(400 MHz, 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).

[0175] Step 2: Synthesis of 2-(difluoromethoxy)-4-fluoroaniline [ka] 2-(Difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, 49.73 mmol) was dissolved in ethanol (80 mL), palladium on carbon (1.0 g, 10% w / w) was added, and the reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 42.99 mmol, yield: 86.42%). ESI-MS: 178.1 [M+1] + .

[0176] Step 3: Synthesis of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline [ka] 2-(Difluoromethoxy)-4-fluoroaniline (8.1 g, 45.73 mmol) was dissolved in concentrated sulfuric acid (40 mL) and potassium nitrate (5.09 g, 50.30 mmol) was added at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours, and the reaction mixture was monitored by TLC. The reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [100% petroleum ether → 15% ethyl acetate] to obtain 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (8.0 g, 35.15 mmol, yield: 76.87%). 1 H NMR(400 MHz, 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).

[0177] Step 4: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 Synthesis of 1,4-methyl-2-nitrobenzene-1,4-diamine [ka] 2-(Difluoromethoxy)-4-fluoro-5-nitroaniline (1 g, 4.50 mmol) was dissolved in acetonitrile (30 mL) and diluted with potassium carbonate (1.24 g, 9.00 mmol) and N 1 ,N 1 ,N 2 5-(difluoromethoxy)-N-trimethylethane-1,2-diamine (0.863 mL, 6.753 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 3 hours and monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography [eluent: dichloromethane / methanol: 0-10%] to give 5-(difluoromethoxy)-N-trimethylethane-1,2-diamine (0.863 mL, 6.753 mmol). The reaction mixture was heated to 80° C. and stirred for 3 hours and monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography [eluent: dichloromethane / methanol: 0-10%] to give 5-(difluoromethoxy)-N-trimethylethane-1,2-diamine (0.863 mL, 6.75 1-(2-(dimethylamino)ethyl)-N 1 -Methyl-2-nitrobenzene-1,4-diamine (1.25 g, 3.74 mmol, yield: 83.03%) was obtained. ESI-MS: 305.2 [M+1] + .

[0178] Intermediate C4-C5 were obtained by referring to the synthesis method of intermediate C3. In step 1, sodium 2-chloro-2,2-difluoroacetate was replaced with iodoethane or isopropyl iodine, and the reaction conditions were changed to stirring at 37°C for 18 hours. TIFF0007628729000132.tif83154

[0179] Preparation of Intermediate C6: N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide [ka] Add N to the reaction flask 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 N-methyl-2-nitrobenzene-1,4-diamine (2.68 g, 10 mmol) and formic acid (20 mL) were added, 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 obtain N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide (2.89 g, yield: 93%). ESI-MS: 296.0 [M+1] + .

[0180] Intermediate C7 was obtained by synthesis according to the synthesis method of intermediate C6: TIFF0007628729000134.tif60154

[0181] Intermediate C8:N 1 -(2-(dimethylamino)ethyl)-N 1Preparation of -methyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene-1,4-diamine [ka]

[0182] Step 1: Synthesis of 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene [ka] 2,4-Difluoro-1-nitrobenzene (12.00 g, 75.43 mmol) and cesium carbonate (24.58 g, 75.43 mmol) were dissolved in tetrahydrofuran (100 mL), and 2,2,2-trifluoroethane-1-ol (5.43 mL, 75.43 mmol) was added at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [eluent: ethyl acetate / petroleum ether: 0-10%] to obtain 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy group)benzene (15.8 g, 64.93 mmol, yield: 86.08%). 1 H NMR (400 MHz, CDCl3) δ 8.03(ddd, J = 9.2, 5.8, 1.1 Hz, 1H), 7.00-6.81(m, 2H), 4.51(qd, J = 7.8, 1.1 Hz, 2H).

[0183] Step 2: Synthesis of 4-fluoro-2-(2,2,2-trifluoroethoxy)aniline [ka] 4-Fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene (15.8 g, 66.08 mmol) was dissolved in ethanol (80 mL) and water (20 mL), iron powder (22.14 g, 396.45 mmol) was added, and the reaction was stirred at 80°C for 5 h and monitored by TLC. The reaction was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated and extracted three times with water and ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [eluent: ethyl acetate / petroleum ether: 0-10%] to give 4-fluoro-2-(2,2,2-trifluoroethoxy)aniline (11.3 g, 52.01 mmol, yield: 78.71%). ESI-MS: 210.1 [M+1] + .

[0184] Step 3: Synthesis of 4-fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)aniline [ka] 4-Fluoro-2-(2,2,2-trifluoroethoxy)aniline (11.3 g, 54.03 mmol) was dissolved in concentrated sulfuric acid (40 mL) and potassium nitrate (6.01 g, 59.43 mmol) was added at 0°C. The reaction mixture was slowly warmed to room temperature, stirred for 3 hours, and monitored by TLC. The reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [eluent: ethyl acetate / petroleum ether: 0-15%] to obtain 4-fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)aniline (6.5 g, 24.29 mmol, yield: 44.97%). 1 H NMR(400 MHz, CDCl3) δ 7.46(d, J = 7.3 Hz, 1H), 6.68(d, J = 11.5 Hz, 1H), 4.47(q, J = 7.7 Hz, 2H), 4.01(s, 2H).

[0185] Process 4:N 1 -(2-(dimethylamino)ethyl)-N 1 Synthesis of -methyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene-1,4-diamine [ka] 4-Fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)aniline (1.0 g, 3.93 mmol) was dissolved in acetonitrile (30 mL) and then added potassium carbonate (1.09 g, 7.87 mmol) and N 1 ,N 1 ,N 2 -trimethylethylene-1,2-diamine (0.754 mL, 5.90 mmol) was added. The reaction mixture was heated to 80°C and stirred for 3 hours and monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography [eluent: dichloromethane / methanol: 0-10%] and N 1 -(2-(dimethylamino)ethyl)-N 1 -Methyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene-1,4-diamine (1.1 g, 3.11 mmol, yield: 79.26%) was obtained. ESI-MS: 337.1 [M+1] + .

[0186] Intermediate C9:N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Preparation of -Methyl-3-nitropyridine-2,5-diamine [ka]

[0187] Step 1: Synthesis of 6-bromo-2-methoxy-3-methylpyridine [ka] Sodium methoxide (5.3 g, 78.0 mmol) was added to a solution of 2,6-dibromo-3-nitropyridine (20 g, 70.9 mmol) in tetrahydrofuran (300 mL) in an ice bath. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was combined, washed with saturated saline, concentrated, and then separated by column chromatography [petroleum ether:ethyl acetate=5:1] to obtain 6-bromo-2-methoxy-3-nitropyridine (13.9 g, yield: 85%). ESI-MS: 217.1 [M-15] + .

[0188] Step 2: 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], iron powder (26.9 g, 480.8 mmol) and ammonium chloride (25.9 g, 480.8 mmol) were added. The reaction solution was stirred at about 90 °C for 3 hours. Dichloromethane and water were added and the mixture was separated. The organic phase was concentrated and then separated by column chromatography [petroleum ether: ethyl acetate = 3:1] to obtain 6-bromo-2-methoxypyridin-3-amine (9.1 g, yield: 75%). ESI-MS: 203.1 [M+1] + . 1 H NMR (400 MHz, 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).

[0189] Step 3: Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)acetamide [ka] Triethylamine (6.7 g, 67.2 mmol, 1.5 eq.) and acetyl chloride (3.8 g, 49.2 mmol, 1.1 eq.) were added to a solution of 6-bromo-2-methoxypyridin-3-amine (9.1 g, 44.8 mmol, 1 eq.) in dichloromethane (200 mL) under ice bath. The reaction mixture was stirred for 1 hour under ice bath. Dichloromethane and water were added to separate the mixture. The organic phase was concentrated and then separated by column chromatography [petroleum ether:ethyl acetate=5:1] to obtain N-(6-bromo-2-methoxypyridin-3-yl)acetamide (9.5 g, yield: 86%), which was used directly in the next step.

[0190] Step 4: 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) under ice bath. The reaction was stirred for 1 hour under ice bath. The reaction solution was slowly poured into ice water and stirred for 1 hour, and a solid was precipitated and filtered under suction. The filter cake was dried to obtain N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (11.5 g, yield: 100%). ESI-MS: 290.1 ​​[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90(s, 1H), 9.12(s, 1H), 4.06(s, 3H), 2.16(s, 3H).

[0191] Step 5: 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 -Trimethylethane-1,2-diamine (520 mg, 5.1 mmol) was added. The reaction solution was stirred at 80°C for 1 hour. After removing the solvent, the product was separated by silica gel column chromatography [dichloromethane:methanol=10:1] to obtain N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide (756 mg, yield: 71%). ESI-MS: 312.3 [M+1] + .

[0192] Process 6:N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 Synthesis of 1,2-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, 7.5 eq.). The reaction solution was stirred at 60°C for 5 hours. The reaction solution was separated by adding a saturated aqueous solution of sodium bicarbonate and dichloromethane. The organic phase was concentrated, and then N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 -Methyl-3-nitropyridine-2,5-diamine (645 mg, yield: 100%) was obtained. ESI-MS: 270.3 [M+1] + .

[0193] Intermediates C10 to C11 were produced with reference to the synthesis method of intermediate C9. TIFF0007628729000147.tif90152

[0194] Intermediate D1:N 1 -(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine [ka] 1-(2-chloropyridin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (250 mg, 0.95 mmol) was dissolved in 20 mL of 1,4-dioxane. The solution was heated at room temperature with N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 1,4-Methyl-2-nitrobenzene-1,4-diamine (254 mg, 0.95 mmol), cesium carbonate (926 mg, 2.85 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (177 mg, 0.285 mmol) and palladium acetate (31 mg, 0.145 mmol) were added. The reaction solution was evacuated and purged with nitrogen three times, and then stirred at 110°C for 2 hours. Water was added to the solution, and the solution was extracted three times with dichloromethane. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After removing the solvent, the mixture was separated by silica gel column chromatography [dichloromethane:methanol = 10:1] and purified by N 1 -(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine (335 mg, yield: 71%) was obtained. ESI-MS: 492.2 [M+1] + .

[0195] Intermediates D2-D46, D47-2, and D48-2 were produced with reference to the synthetic method of intermediate D1. TIFF0007628729000149.tif240160 TIFF0007628729000150.tif190160 TIFF0007628729000151.tif242160 TIFF0007628729000152.tif191160 TIFF0007628729000153.tif184160 TIFF0007628729000154.tif200160 TIFF0007628729000155.tif193160 TIFF0007628729000156.tif192160 TIFF0007628729000157.tif193160 TIFF0007628729000158.tif184160 TIFF0007628729000159.tif242160 TIFF0007628729000160.tif198160 TIFF0007628729000161.tif231160 TIFF0007628729000162.tif198160

[0196] Preparation of intermediate D49-1: 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine [ka] A reaction flask was charged with 1-(2-chloropyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (235 mg, 0.86 mmol), 4-fluoro-2-methoxy-5-nitroaniline (159.38 mg, 0.81 mmol), cesium carbonate (440.50 mg, 1.28 mmol), and palladium acetate (20.24 mg, 0.09 mmol). 1,1'-bisnaphthalene-2,2'-bisdiphenylphosphine (112.24 mg, 0.17 mmol) and 1,4-dioxane (15 mL) were added in sequence, the reaction solution was purged with nitrogen three times, and the mixture was stirred at 120°C for 2 hours under nitrogen gas protection, filtered, the filtrate was concentrated, and the residue was separated by column chromatography [methanol / dichloromethane: 0-10%] to obtain 4-(3,3-dimethyl-2,3-dihydro-1H-pyrroly[3,2-b]pyridin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (349 mg, yield: 89.38%). ESI-MS: 411.0 [M+1] + .

[0197] Intermediates D50-1 and D51-1 were produced with reference to the synthesis method of intermediate D49-1. TIFF0007628729000164.tif120150

[0198] Intermediate D49: Preparation of (R)-4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)pyrimidin-2-amine [ka] (R)-N,N-dimethyl-1-(pyrrolidin-2-yl)methanamine (93.12 mg, 0.44 mmol) and N,N-diisopropylethylamine (149.30 mg, 1.16 mmol) were added to a solution (100 mg, 0.23 mmol) of 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine in 1,4-dioxolane (20 mL). The reaction mixture was stirred at 120° C. for 18 hours. Dichloromethane and water were added to separate the mixture. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [dichloromethane:methanol=10:1] to give (R)-4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (115 mg, yield: 91.01%). ESI-MS: 519.2 [M+1] + .

[0199] Intermediates D50 to D52 were obtained by producing them with reference to the synthetic method of intermediate D49. TIFF0007628729000166.tif184153

[0200] Preparation of intermediate D53-1: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-amine [ka]

[0201] Step 1: Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine [ka] At room temperature, 2,4-dichloro-1,3,5-triazine (9.67 g, 64.46 mmol) was dissolved in dichloromethane (150 mL), and 4-fluoro-2-methoxy-5-nitroaniline (10 g, 53.72 mmol) and N,N-diisopropylethylamine (13.86 g, 107.44 mmol) were added in sequence. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain a crude product, which was then added with dichloromethane (80 mL), stirred for 30 minutes, and filtered. The obtained filter cake was washed twice with dichloromethane and dried to obtain 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine (10.15 g, yield: 63%), ESI-MS. 300.1 [M+1] + .

[0202] Step 2: Synthesis of N-(4-)fluoro-2-methoxy-5-nitrophenyl)-4-(3,3,5-trimethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-amine [ka] To a solution of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.63 mol) in 1,4-dioxane (20 mL) was added 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine (185 g, 0.63 mmol, 1 eq.) and p-toluenesulfonic acid monohydrate (143 mg, 0.75 mmol). The reaction mixture was stirred at 120°C for 2 hours. Dichloromethane and water were added to separate the mixture. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(3,3,5-trimethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-amine, which was used directly in the next reaction. ESI-MS: 426.2 [M+1]+ .

[0203] Intermediates D54-1 to D64-1 were produced with reference to the synthesis method of intermediate D53-1. TIFF0007628729000170.tif190160 TIFF0007628729000171.tif234160 TIFF0007628729000172.tif175160 TIFF0007628729000173.tif76160

[0204] Intermediate D53:N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitro-N 4 Preparation of -(4-(3,3,5-trimethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine [ka] To a solution of the crude product of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-amine in 1,4-dioxane (100 mL), dimethyl[2-(methylamino)ethyl]amine (95 mg, 0.95 mmol) and diisopropylethylamine (82 mg, 0.95 mmol) were added. The reaction mixture was stirred at 120°C for 18 hours. Dichloromethane and water were added to separate the layers. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography [dichloromethane:methanol=10:1]. 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitro-N 4-(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine (130 mg) was obtained. ESI-MS: 508.2 [M+1] + .

[0205] Intermediates D54-D63 and D64-2 were produced with reference to the synthetic method of intermediate D53. TIFF0007628729000175.tif216160 TIFF0007628729000176.tif199160 TIFF0007628729000177.tif242160 TIFF0007628729000178.tif75160

[0206] Intermediate D47:N 1 -(2-(dimethylamino)ethyl)-N 4 -(4-(1,5'-dimethylspiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)pyrimidin-2-yl)-5 methoxy-N 1 -Methyl-2-nitrobenzene-1,4-diamine [ka] tert-Butyl 1'-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)ami)pyrimidin-4-yl)-5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (50 mg, 0.079 mmol) and trifluoroacetic acid (3 mL) were dissolved in methylene chloride (10 mL). The reaction solution was stirred at room temperature for 30 minutes, and after the reaction was completed, it was concentrated to dryness, and the residue was dissolved in methanol (3 mL) and water (20 mL). To the reaction mixture, an aqueous formaldehyde solution (5 mL) and diisopropylethylamine (51 mg, 0.39 mmol) were added, and the reaction mixture was stirred for 10 minutes. Then, sodium cyanoborohydride (50 mg, 0.80 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was separated and extracted with dichloromethane (50 mL) and water (50 mL). The organic phase was dried and concentrated, and then extracted with N 1 -(2-(Dimethylamino)ethyl)-N 4 -(4-(1,5'-dimethylspiro[pyrrolo-3,3'-pyrrolo[3,2-b]pyridin]-1'(2'H)-yl)pyrimidin-2-yl)-5-methoxy-N 1 -Methyl-2-nitrobenzene-1,4-diamine (40 mg, 0.073 mmol, yield: 92.57%) was obtained. ESI-MS: 518.2 [M+1] + .

[0207] Intermediates D48 and D64 were produced with reference to the synthetic method of intermediate D47. TIFF0007628729000180.tif159160

[0208] Intermediate D65: 2-(difluoromethoxy)-N 4 -(2-(dimethylamino)ethyl)-N 4 -Methyl-5-nitro-N 1 Preparation of -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine [ka] A solution of 1-(4-chloro-1,3,5-triazin-2-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (150 mg, 0.54 mmol) in 1,4-dioxane (10 mL) was added with 5-(difluoromethoxy)-N 1 -(2-(Dimethylamino)ethyl)-N 1 1,4-Methyl-2-nitrobenzene-1,4-diamine (166 mg, 0.54 mmol) and p-toluenesulfonic acid monohydrate (125 mg, 0.54 mmol) were added. The reaction mixture was stirred at 120°C for 2 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the mixture was separated. The organic phase was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by silica gel column chromatography [dichloromethane:methanol=10:1] to obtain 2-(difluoromethoxy)-N 4 -(2-(dimethylamino)ethyl)-N 4 -Methyl-5-nitro-N 1 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine (200 mg, yield: 67%) was obtained. ESI-MS: 544.1 [M+1] + .

[0209] Intermediate D66 was obtained by producing with reference to the synthetic method of intermediate D65. TIFF0007628729000182.tif93160

[0210] Intermediate D67:N 1 -(2-(dimethylamino)ethyl)-5-ethoxy group-N 1 -Methyl-2-nitro-N 4 Preparation of -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine [ka] A solution of 1-(4-chloro-1,3,5-triazin-2-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (150 mg, 0.54 mmol) in n-butanol (10 mL) was added to 1 -(2-(dimethylamino)ethyl)-5-ethoxy group-N 1 1,4-Methyl-2-nitrobenzene-1,4-diamine (153.6 mg, 0.54 mmol) and trifluoroacetic acid (124 mg, 1.09 mmol) were added. The reaction mixture was stirred at 120°C for 2 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the mixture was separated. The organic phase was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by silica gel column chromatography [dichloromethane:methanol = 10:1]. 1 -(2-(dimethylamino)ethyl)-5-ethoxy group-N 1 -Methyl-2-nitro-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine (220 mg, yield: 62.8%) was obtained. ESI-MS: 522.3 [M+1] + .

[0211] Intermediates D68 to D70 were obtained by producing them with reference to the synthetic method of intermediate D67. TIFF0007628729000184.tif217160

[0212] Intermediate D71:N 1 -(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine [ka] N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide (309.28 mg, 1.04 mmol) was dissolved in N,N-dimethylacetamide (20 mL). Sodium hydride (62 mg, 1.57 mmol) was added to the reaction solution at 0°C. The reaction solution was stirred at room temperature for 20 minutes. 5-Bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (400 mg, 1.04 mmol) was added and stirring was continued for 2 hours. A small amount of water was added to the reaction solution and the mixture was stirred for 1 hour. After the reaction was completed, ethyl acetate and water were added and the mixture was separated. The organic phase was washed with water and saturated sodium chloride in that order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether:ethyl acetate=4:1]. 1 -(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine (543 mg, yield: 91.2%) was obtained. ESI-MS: 571.2, 573.2 [M+1] + .

[0213] Intermediate D72 was obtained by producing with reference to the synthetic method of intermediate D71. TIFF0007628729000186.tif85160

[0214] Intermediate E1:N 4 -(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Production of methylbenzene-1,2,4-triamine [ka] N 1-(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 1,4-Methyl-5-nitrobenzene-1,4-diamine (335 mg, 0.68 mmol) was dissolved in a 20 mL / 10 mL mixture of ethanol / water. Iron powder (228 mg, 4.08 mmol) and ammonium chloride (228 mg, 4.08 mmol) were added to the solution at room temperature. The reaction solution was stirred at 90°C for 3 hours. Water was added to the solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After removing the solvent, N 4 -(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methylbenzene-1,2,4-triamine (205 mg, yield: 65%) was obtained. ESI-MS: 462.4 [M+1] + .

[0215] Intermediates E2 to E29 were obtained by producing them with reference to the synthetic method of intermediate E1. TIFF0007628729000188.tif203160 TIFF0007628729000189.tif239160 TIFF0007628729000190.tif191160 TIFF0007628729000191.tif202160 TIFF0007628729000192.tif200160 TIFF0007628729000193.tif234160 TIFF0007628729000194.tif232160 TIFF0007628729000195.tif199160 TIFF0007628729000196.tif69160

[0216] Intermediate E30:N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)benzene-1,2,4-triamine TIFF0007628729000197.tif3656N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitro-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)benzene-1,4-diamine (201 mg, 0.40 mmol) was dissolved in 5 mL of methanol. 10% palladium on carbon (20 mg) was added to this solution. The reaction solution was purged with hydrogen three times and stirred at room temperature under a hydrogen gas atmosphere for 3 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth. After removing the solvent, N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (150 mg, yield: 79.3%) was obtained. ESI-MS: 477.3 [M+1] + .

[0217] Intermediates E31-E68 were obtained by producing them with reference to the synthetic method of intermediate E30. TIFF0007628729000198.tif216160 TIFF0007628729000199.tif206160 TIFF0007628729000200.tif207160 TIFF0007628729000201.tif199160 TIFF0007628729000202.tif216160 TIFF0007628729000203.tif207160 TIFF0007628729000204.tif199160 TIFF0007628729000205.tif208160 TIFF0007628729000206.tif199160 TIFF0007628729000207.tif201160 TIFF0007628729000208.tif199160 TIFF0007628729000209.tif215160 TIFF0007628729000210.tif141160

[0218] Intermediate E69: 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 -Methyl-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine [ka] 2-(Difluoromethoxy)-N 4 -(2-(dimethylamino)ethyl)-N 4 -Methyl-5-nitro-N 1 To a solution of -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,4-diamine (200 mg, 0.37 mmol) in methanol (6 mL), zinc powder (482 mg, 7.36 mmol) and ammonium chloride (394 mg, 7.36 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through diatomaceous earth, concentrated, and separated by silica gel column chromatography [dichloromethane:methanol=10:1] to obtain 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1-Methyl-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine (87 mg, yield: 42%) was obtained. ESI-MS: 514.1 [M+1] + .

[0219] Intermediate E70 was obtained by producing with reference to the synthetic method of intermediate E69. TIFF0007628729000212.tif85160

[0220] Preparation of intermediate F1: N-(5-(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] N 4 -(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1N,N-Methylbenzene-1,2,4-triamine (194 mg, 0.36 mmol) was dissolved in anhydrous acetonitrile / water (3 mL / 1 mL). To this solution was added N,N-diisopropylethylamine (138 mg, 1.08 mmol). To the reaction solution was added acryloyl chloride (97.3 mg, 1.08 mmol) at 0°C. After the reaction was completed, dichloromethane and water were added to separate the layers, and 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 chromatography [40-50% acetonitrile / water] to obtain N-(5-(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(meth)amino)-4-methoxyphenyl)acrylamide (150 mg, yield: 56.2%). ESI-MS: 595.2, 597.2 [M+1] + .

[0221] Intermediate F2 was obtained by producing with reference to the synthetic method of intermediate F1. TIFF0007628729000214.tif86160

[0222] Intermediate G1: Preparation of N-(5-(4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] N-(5-(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (150 mg, 0.2 mmol), trimethylethynylsilyl (247 mg, 2.5 mmol), triethylamine (509 mg, 5.0 mmol), bis(triphenylphosphine)palladium dichloride (58 mg, 0.076 mmol) and cuprous iodide (14.4 mg, 0.076 mmol) were dissolved in tetrahydrofuran (6 mL), and the reaction solution was stirred at room temperature under nitrogen gas protection for 3 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated on a flash silica gel column [dichloromethane:methanol=10:1] to give N-(5-((4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (100 mg, yield: 27.86%). ESI-MS: 613.4 [M+1] + .

[0223] Intermediate G2 was obtained by producing with reference to the synthetic method of intermediate G1. TIFF0007628729000216.tif100160

[0224] II. Preparation of the Compounds of Specific Examples Example 1: Preparation of N-(5-((4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] N 4-(4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 N,N-Methylbenzene-1,2,4-triamine (205 mg, 0.44 mmol) was dissolved in anhydrous dichloromethane (5 mL). To this solution was added N,N-diisopropylethylamine (170 mg, 1.32 mmol). To the reaction solution was added acryloyl chloride (67 mg, 0.75 mmol) at 0°C. After concentration, the mixture was separated by reverse phase chromatography [40-50% acetonitrile / water] to obtain N-(5-((4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (8.1 mg, yield: 3.5%). ESI-MS: 516.2 [M+1] + . 1 H NMR(400 MHz, DMSO-d6) δ 10.10(s, 1H), 8.82(s, 1H), 7.96(d, J = 5.2 Hz, 2H), 7.81(s, 1H), 7.68(d, J = 8.2 Hz, 1H), 7.09(dd, J = 8.2, 4.8 Hz, 1H), 6.97(s, 1H), 6.80(s, 1H), 6.60(d, J = 5.7 Hz, 1H), 6.38(dd, J = 16.9, 10.0 Hz, 1H), 6.22(d, J = 16.8 Hz, 1H), 5.74(d, J = 9.9 Hz, 1H), 3.84(s, 3H), 3.80(s, 2H), 2.85(t, J = 7.9 Hz, 2H), 2.68(s, 3H), 2.27(t, J = 7.9 Hz,2H), 2.19(s, 6H), 1.32(s, 6H).

[0225] Example 9: Preparation of N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide [ka] 5-(Difluoromethoxy)-N 1 -(2-(Dimethylamino)ethyl)-N 1 -Methyl-N 4 -(4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine (87 mg, 0.17 mmol) was dissolved in acetonitrile / water (4:1, 5 mL). To this solution was added N,N-diisopropylethylamine (66 mg, 0.51 mmol). Acryloyl chloride (23 mg, 0.25 mmol) was added to the reaction solution at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was quenched with 0.5 mL of methanol, and then subjected to high performance liquid chromatography to obtain N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (47.8 mg, yield: 48%). ESI-MS: 568.2 [M+1] + . 1H NMR(400 MHz, DMSO-d6) δ 10.19(s, 1H), 9.16(d, J = 209.4 Hz, 1H), 8.39(d, J = 24.2 Hz, 2H), 7.34-6.65(m, 3H), 6.44(dd, J = 16.9, 10.1 Hz, 1H), 6.25(t, J = 17.4 Hz, 1H), 5.79(d, J = 10.1 Hz, 1H), 3.97(d, J = 30.7 Hz, 2H), 2.87(s, 2H), 2.72(s, 3H), 2.37(t, J = 17.7Hz, 5H), 2.21(s, 6H), 1.29(s, 6H).

[0226] The following compounds were produced with reference to the synthesis methods of Example 1 or Example 9. TIFF0007628729000219.tif210160 TIFF0007628729000220.tif191160 TIFF0007628729000221.tif208160 TIFF0007628729000222.tif199160 TIFF0007628729000223.tif192160 TIFF0007628729000224.tif200160 TIFF0007628729000225.tif207160 TIFF0007628729000226.tif207160 TIFF0007628729000227.tif200160 TIFF0007628729000228.tif207160 TIFF0007628729000229.tif192160 TIFF0007628729000230.tif209160 TIFF0007628729000231.tif214160 TIFF0007628729000232.tif207160 TIFF0007628729000233.tif208160 TIFF0007628729000234.tif216160 TIFF0007628729000235.tif207160 TIFF0007628729000236.tif216160 TIFF0007628729000237.tif207160 TIFF0007628729000238.tif224160 TIFF0007628729000239.tif207160 TIFF0007628729000240.tif200160 TIFF0007628729000241.tif77160

[0227] The NMR data of the compounds obtained in the above examples are as follows. TIFF0007628729000242.tif206160 TIFF0007628729000243.tif232160 TIFF0007628729000244.tif165160 TIFF0007628729000245.tif208160 TIFF0007628729000246.tif241160 TIFF0007628729000247.tif231160 TIFF0007628729000248.tif224160 TIFF0007628729000249.tif207160 TIFF0007628729000250.tif207160 TIFF0007628729000251.tif233160 TIFF0007628729000252.tif239160 TIFF0007628729000253.tif222160 TIFF0007628729000254.tif200160 TIFF0007628729000255.tif182160 TIFF0007628729000256.tif233160 TIFF0007628729000257.tif181160 TIFF0007628729000258.tif125160

[0228] Example 54: Preparation of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-ethynyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide [ka] N-(5-((4-(3,3-dimethyl-5-((trimethylsilyl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (100 mg, 0.07 mmol) was dissolved in methanol (5 mL) and potassium carbonate (19.3 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 1 hour, filtered, and the solvent was removed from the filtrate. The residue was then separated by reverse phase chromatography [40-50% acetonitrile / water] to give N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-ethynyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (3.3 mg, yield: 7.83%). ESI-MS: 541.2 [M+1] + . 1H NMR(400MHz, DMSO-d6) δ 10.05(s, 1H), 8.51(s, 1H), 8.26-8.08(m, 3H), 7.10(d,J = 8.4 Hz, 1H), 7.02(s, 1H), 6.41(dd,J = 16.9, 10.1 Hz, 1H), 6.29(d,J = 5.8 Hz, 1H), 6.17(dd,J = 16.9, 2.1 Hz, 1H), 5.72(dd,J = 10.1, 2.0 Hz, 1H), 4.13(s, 1H), 3.86(s, 2H), 3.77(s, 3H), 2.90(t,J = 5.9 Hz, 2H), 2.73(s, 3H), 2.33(t,J = 5.9 Hz, 2H), 2.21(s, 6H), 1.31(s, 6H).

[0229] Example 68 was produced with reference to the synthesis method of Example 54. TIFF0007628729000260.tif93160

[0230] The NMR data of the compounds obtained in the above examples are as follows. TIFF0007628729000261.tif62160

[0231] Example 58: Preparation of N-(5-(4-(3,3-dimethyl-5-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka]

[0232] Step 1: Synthesis of tert-butyl 4-(1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate [ka] Add N to the reaction flask 1 -(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(Dimethylamino)ethyl)-2-methoxy-N 4 ‐Methyl-5‐nitrobenzene‐1,4‐diamine (40 mg, 0.67 mmol), tert‐butyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaboropentan‐2‐yl)‐1H‐pyrazole‐1‐carboxylate (19.6 mg, 0.67 mmol), potassium phosphate (42 mg, 2.0 mmol), tricyclohexylphosphine (7.5 mg, 0.03 mmol), palladium acetate (3.0 mg, 0.013 mmol), and toluene (3 mL) were added. The mixture was purged with nitrogen three times and heated to 110 °C under nitrogen gas protection and stirred for 16 h. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated on a flash silica gel column [eluent: ethyl acetate / petroleum ether: 0-30%] to obtain tert-butyl 4-(1-(2-(4-(2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (36 mg, yield: 78.1). ESI-MS: 659.3 [M+1] + .

[0233] Step 2: Synthesis of tert-butyl 4-(1-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate [ka] tert-Butyl 4-(1-(2-((4-(2-(dimethylamino)ethyl)(meth)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (36 mg, 0.055 mmol) was dissolved in 5 mL of methanol. To this solution was added 10% palladium on carbon (10 mg). The reaction solution was purged with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 1 hour. After completion of the reaction, the solution was filtered through diatomaceous earth. After removing the solvent, tert-butyl 4-(1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (30 mg, yield: 82.1%) was obtained. ESI-MS: 629.4 [M+1] + .

[0234] Step 3: Synthesis of tert-butyl 4-(1-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(meth)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate [ka] tert-Butyl 4-(1-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (30 mg, 0.048 mmol) was dissolved in anhydrous acetonitrile / water (1 mL / 0.3 mL). To this solution was added N,N-diisopropylethylamine (18 mg, 0.143 mmol). To the reaction solution was added acryloyl chloride (13.0 mg, 0.143 mmol) at 0°C. After the reaction was completed, dichloromethane and water were added to separate the mixture. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by reverse phase chromatography [40-50% acetonitrile / water] to obtain tert-butyl 4-(1-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(meth)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (300 mg, yield: 64.5%). ESI-MS: 683.4 [M+1] + .

[0235] Step 4: Synthesis of N-(5-(4-(3,3-dimethyl-5-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] tert-Butyl 4-(1-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(meth)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrazole-1-carboxylate (30 mg, 0.044 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction was stirred at room temperature for 2 h, the solvent was removed, and the residue was subjected to reverse phase chromatography to obtain N-(5-(4-(3,3-dimethyl-5-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(meth)amino)-4-methoxyphenyl)acrylamide (5 mg, yield: 18.5%). ESI-MS: 583.3 [M+1] + . 1 HNMR(400MHz, DMSO-d6) δ 12.92(s, 1H), 10.03(s, 1H), 8.59(s, 1H), 8.27(d,J = 8.4 Hz, 1H), 8.12(d,J = 5.8 Hz, 2H), 8.05(s, 1H), 7.91(s, 1H), 7.22(d,J = 8.4 Hz, 1H), 7.02(s, 1H), 6.44(dd,J = 16.9, 10.1 Hz, 1H), 6.28(d,J = 5.8 Hz, 1H), 6.17(dd,J = 16.8, 2.1 Hz, 1H), 5.70(dd,J = 10.1, 2.1 Hz, 1H), 3.86(s, 2H), 3.80(s, 3H), 2.92(t,J = 6.0 Hz, 2H), 2.75(s, 3H), 2.39-2.31(m, 2H), 2.20(s, 6H), 1.35(s, 6H).

[0236] Example 59: Preparation of N-(5-((4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka]

[0237] Process 1:N 1 -(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine and N 1 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 Synthesis of -methyl-5-nitrobenzene-1,4-diamine [ka] Add N to the reaction flask 1 -(4-(5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(Dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine (100 mg, 0.166 mmol), 4-methyl-1H-imidazole (13.7 mg, 0.166 mmol), potassium carbonate (68.9 mg, 0.5 mmol), cuprous iodide (6.3 mg, 0.033 mmol), (1S,2S)-N 1 ,N 21,2-Dimethylcyclohexane-1,2-diamine (9.5 mg, 0.066 mmol) and dimethyl sulfoxide (2 mL) were added. The mixture was purged with nitrogen three times, and heated to 110°C under nitrogen gas protection and stirred for 16 hours. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated on a flash silica gel column [eluent: methanol / dichloromethane: 0-10%] and purified with N 1 -(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine (19 mg, yield: 18.1%) was obtained. ESI-MS: 287.0 [M+1] + . N 1 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl)-2-methoxy-N 4 -Methyl-5-nitrobenzene-1,4-diamine (53 mg, yield: 50.4%) ESI-MS: 287.1 [M+1] + .

[0238] Process 2:N 4 -(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 Synthesis of -methylbenzene-1,2,4-triamine [ka] N 1-(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(Dimethylamino)ethyl)-2-methoxy-N 4 1,4-Methyl-5-nitrobenzene-1,4-diamine (17 mg, 0.055 mmol) was dissolved in 5 mL of methanol. 10% palladium on carbon (10 mg) was added to this solution. The reaction mixture was purged with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was complete, the mixture was filtered through diatomaceous earth. After removing the solvent, N 4 -(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methylbenzene-1,2,4-triamine (10 mg, yield: 56.5%) was obtained. ESI-MS: 543.2 [M+1] + .

[0239] Step 3: Synthesis of N-(5-((4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] N 4 -(4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1N,N-Methylbenzene-1,2,4-triamine (10 mg, 0.018 mmol) was dissolved in anhydrous acetonitrile / water (1 mL / 0.3 mL). To this solution was added N,N-diisopropylethylamine (7 mg, 0.055 mmol). To the reaction solution was added acryloyl chloride (5 mg, 0.055 mmol) at 0°C. After the reaction was completed, dichloromethane and water were added to separate the mixture. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by reverse phase chromatography [40-50% acetonitrile / water] to obtain N-(5-((4-(3,3-dimethyl-5-(5-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (1.7 mg, yield: 14.7%). ESI-MS: 597.4 [M+1] + . 1 HNMR(DMSO-d6) δ 9.61(s, 1H), 9.29(s, 1H), 8.53(d,J = 8.6 Hz, 1H), 8.28(s, 1H), 8.24-8.15(m, 2H), 7.89(s, 1H), 7.17(d,J = 8.5 Hz, 1H), 6.82(s, 1H), 6.60(dd,J = 16.6, 10.4 Hz, 1H), 6.33(d,J = 5.9 Hz, 1H), 6.23(dd,J = 16.8, 2.0 Hz, 1H), 5.73(dd,J = 10.1, 2.0Hz, 1H), 3.93(s, 2H), 3.85(s, 3H), 3.25(s, 2H), 2.76(s, 6H), 2.64(s, 3H), 2.52(s, 2H), 2.29(s, 3H), 1.36(s, 6H).

[0240] Example 60: Preparation of N-(5-((4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka]

[0241] Process 1:N 4 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 Synthesis of -methylbenzene-1,2,4-triamine [ka] N 1 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 4 -(2-(Dimethylamino)ethyl)-2-methoxy-N 4 1,4-Methyl-5-nitrobenzene-1,4-diamine (53 mg, 0.093 mmol) was dissolved in 5 mL of methanol. 10% palladium on carbon (10 mg) was added to this solution. The reaction mixture was purged with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth. After removing the solvent, N 4 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methylbenzene-1,2,4-triamine (32 mg, yield: 61.8%) was obtained. ESI-MS: 543.2 [M+1]+ .

[0242] Step 2: Synthesis of N-(5-((4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide [ka] N 4 -(4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 N,N-Methylbenzene-1,2,4-triamine (32 mg, 0.059 mmol) was dissolved in anhydrous acetonitrile / water (1 mL / 0.3 mL). To this solution was added N,N-diisopropylethylamine (22.8 mg, 0.177 mmol). To the reaction solution was added acryloyl chloride (16 mg, 0.177 mmol) at 0°C. After the reaction was completed, dichloromethane and water were added to separate the mixture. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by reverse phase chromatography [40-50% acetonitrile / water] to obtain N-(5-((4-(3,3-dimethyl-5-(4-methyl-1H-imidazol-1-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (13 mg, yield: 35.1%). ESI-MS: 597.3 [M+1] + . 1HNMR(400MHz, DMSO-d6) δ 9.98(s, 1H), 8.55(s, 1H), 8.48(d,J = 8.7 Hz, 1H), 8.26(d,J = 1.4 Hz, 1H), 8.20-8.11(m, 2H), 7.52(t,J = 1.3 Hz, 1H), 7.23(d,J = 8.7 Hz, 1H), 7.01(s, 1H), 6.43(dd,J = 16.9, 10.1 Hz, 1H), 6.28(d,J = 5.8 Hz, 1H), 6.16(dd,J = 16.9, 2.1Hz, 1H), 5.68(dd,J = 10.1, 2.1 Hz, 1H), 3.90(s, 2H), 3.80(s, 3H), 2.91(s, 2H), 2.75(s, 3H), 2.33(d,J = 6.1 Hz, 2H), 2.25-2.15(m, 9H), 1.36(s, 6H).

[0243] Biological measurements and evaluation 1. Cell proliferation experiment (i) Reagents and consumables Fetal bovine serum (FBS) (GBICO, Cat#10099-141), CellTiter-Glo® Luminescent Cell Viability Detection Kit (Promega, Cat#G7572), Black clear flat bottom 96 well plate (Corning®, Cat# 3603).

[0244] (ii) equipment; SpectraMax PerkinElmer MD, 2104-0010A, Thermo Scientific 3100 Series CO2 Incubator, Thermo Scientific, 1300 Series Type A2 Biological Safety Cabinet, Olympus CKX41SF inverted microscope, Siemens KK25E76TI refrigerator.

[0245] (iii) Cell lines and culture conditions TIFF0007628729000274.tif40160

[0246] (iv) Experimental procedure 1. Cell culture and seeding Logarithmic growth phase cells were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion dye exclusion to ensure that cell viability was 90% or higher. The cell concentration was adjusted to the final density, and 90 μL of the cell suspension was added to a 96-well plate. Cells were incubated overnight in 96-well plates at 37°C, 5% CO2, and 95% humidity.

[0247] 2. T0 Reference Data: 10 μL of PBS was added to each well of the T0 plate containing cells. The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature (30 min). An equal volume of CTG solution was added to each well. The cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plate was left at room temperature for 20 min to stabilize the luminescence signal. The T0 luminescence signal was read.

[0248] 3. Compound dilution and addition According to the compound information sheet, a corresponding amount of DMSO was added to the corresponding compound powder to prepare a 10 mM stock solution. Compound solutions diluted 1000-fold and 3.16-fold were prepared. The compound solution diluted 1000-fold was diluted 100-fold with PBS to prepare 10-fold compound solutions with 9 concentrations, the highest concentration of 10 μM, and then diluted 3.16-fold to add 10 μL of the drug solution to each well of a 96-well plate and seed the cells. Three duplicate wells were prepared for each compound concentration, and the final concentration of DMSO was 0.1%. The cells were placed in a 96-well plate containing the drug and cultured for 72 hours under conditions of 37°C, 5% CO2, and 95% humidity, after which CTG analysis was performed.

[0249] 4. Reading the luminescence signal The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature (30 min). An equal volume of CTG solution was added to each well. The cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plate was left at room temperature for 20 min to stabilize the luminescence signal. The luminescence signal was read. 5. Data Processing The data were analyzed using GraphPad Prism 7.0 software, and a curve was fitted to the data using the S-curve fitting method to obtain a dose-response curve, based on which the IC 50 The values ​​(unit: nM) were calculated, and the specific experimental results are shown in Table 1. Cell viability (%)=(Lum test drug-Lum medium control) / (Lum cell control-Lum medium control)×100%.

[0250] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0251] The biological activity data of the compounds in the specific examples show that a series of compounds of the present invention have strong inhibitory effects on EGFR exon 20 insertion mutation at the cellular level and have high selectivity against EGFR WT. Under the same test conditions, the cytostatic activity of the compounds in some examples of the present invention is several times higher than that of the positive compounds.

[0252] All documents mentioned in this application are incorporated by reference as if each of the documents was individually incorporated by reference. It should be understood that after reading the above disclosure of the present invention, a person skilled in the art may make numerous changes or modifications to the present invention, and such equivalents are within the scope defined by the appended claims of this application.

Claims

1. Formula (IIIa 1 ): 【Chemistry 1】 (In the formula: R 2 and R 3 are independently hydrogen, deuterium, halogen, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 or R is selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclic group; 2 and R 3 C together with the carbon atom directly bonded to them 3-6 Forming a cycloalkyl group or a 3- to 6-membered heterocyclic group, R 4 are hydrogen, deuterium, and C 1-4 Alkyl group, C 3-6 The C 1-4 alkyl group and the C 3-6 cycloalkyl group may optionally further comprise deuterium, halogen, a hydroxyl group, a cyano group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 may be substituted with one or more substituents selected from the group consisting of a cycloalkoxy group, a 3- to 6-membered heterocyclic group, and a 3- to 6-membered heterocyclic oxy group; R 5 , R 7 and R 8 are each independently a hydrogen atom or a methyl group; R 9a 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 and 3- to 6-membered heterocyclic groups) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

2. R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; or R 2 and R 3 together with the carbon atom directly bonded thereto form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxepentyl or azepentyl group, R 4 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; R 5 , R 7 and R 8 are each independently a hydrogen atom or a methyl group; R 9a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl and cyclobutyl. 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

3. A compound represented by the formula: 【Chemistry 2】 The compound according to any one of claims 1 to 2, characterized in that it is selected from the group consisting of 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

4. The following process 【Chemistry 3】 (where X 1 is selected from the group consisting of fluorine, chlorine and bromine; R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9ａ is as defined in claim 1) The compound according to claim 1, characterized in that it comprises 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 3, 1 ) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

6. A compound of formula (IIIa) according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment and / or prevention of cancer, tumors or metastatic diseases, at least some of which are associated with EGFR exon 20 insertions, deletions or other mutations. 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

7. A compound of formula (IIIa) according to any one of claims 1 to 3 in the manufacture of a medicament for the prevention and / or treatment of tumors, cancer and metastatic diseases due to disorders inducing hyperproliferation and cell death. 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

8. The use of a compound of formula (IIIa) according to any one of claims 1 to 3 in the manufacture of a medicament for the prevention and / or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, breast tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal sinus inverted papilloma or intranasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma, at least some of which are associated with EGFR exon 20 insertions, deletions or other mutations. 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

9. The use of a compound according to any one of claims 1 to 3 in the prevention and / or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphomas, head and neck tumors, breast tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma. 1 ) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

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