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

Abstract

It relates to 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, their preparation methods and applications. In particular, it relates to an EGFR inhibitor having the structure of formula (I), its preparation method, a pharmaceutical composition containing the same, and its use as an EGFR inhibitor and its use in the treatment and / or prevention of cancers, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertions or deletions, especially in the treatment of hyperproliferative diseases and the induction of diseases with cell death disorders. Each substituent of formula (I) is the same as the definition in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivatives, a preparation method thereof, and applications thereof. Background Art

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

[0003] Although classical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M) have been successfully inhibited, in-frame insertions in exon 20 also lead to constitutive activation of EGFR signaling and are associated with de novo resistance to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogene driver mutations and are enriched in women, non-smokers, Asian populations, and adenocarcinomas of NSCLC patients. In addition to NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, namely nasal squamous cell carcinoma (SNSCC). Furthermore, structurally similar exon 20 insertion mutations have also been found in another member of the receptor tyrosine kinase (RTK) EGFR family, HER2.

[0004] Multiple retrospective analyses have shown that currently available first-generation, second-generation, 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. Several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in patients with EGFR exon 20 non-small cell lung cancer. However, due to limited selectivity for EGFR WT (wild type), their adverse reactions are inevitable and 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 a 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine derivative, a preparation method thereof and an application. The series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutations, and have high selectivity for EGFR wild type, and can be widely used in the preparation of drugs for treating and / or preventing at least some cancers, tumors or metastatic diseases related to EGFR exon 20 insertion, deletion or other mutations, especially drugs for treating hyperproliferative diseases and inducing cell death disorder diseases, and thus are expected to develop a new generation of EGFR inhibitors.

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

[0007]

[0008] Wherein, X and Y are each independently CR 10 or N; Z is CR 11 or N; Q is CH or N;

[0009] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10Alkyl, C 3-12 Cycloalkyl, 3 - 12 - membered heterocyclic group, C 6-10 Aryl, 5 - 10 - membered heteroaryl, ═O, -SF5, -S(O) r R 12 , -O - R 13 , -C(O)OR 13 , -C(O)R 14 , -O - C(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 substituted by the substituents of,

[0010] Alternatively, when m≥1, R1 and the adjacent R9 together with the part directly connected thereto form a C 5-6 cycloalkyl or a 5 - 6 - membered heterocyclic group;

[0011] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 - 12 - membered heterocyclic group, C 6-10 aryl and 5 - 10 - membered heteroaryl,

[0012] Alternatively, R2 and R3 together with the carbon atom directly connected thereto form a C 3-6 cycloalkyl or a 3 - 6 - membered heterocyclic group, and the above - mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen - substituted C 1-10 alkyl, deuterium - substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3 - 12 - membered heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, ═O, -SF5, -S(O) r R 12 , -O - R 13 , -C(O)OR 13 , -C(O)R 14 , -O - C(O)R 14 , -NR15 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 substituted by a substituent;

[0013] R4 is selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 substituted by a substituent;

[0014] R5 is selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group;

[0015] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R16 , -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 ;

[0016] Alternatively, R5 and the moiety directly attached thereto together form a 4- to 6-membered heterocyclic group, and the above-mentioned 4- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0017] R7 and R8 are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, or R7 and the nitrogen atom directly attached thereto together form a 3- to 12-membered heterocyclic group, and the above-mentioned groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3 - 12 membered heterocyclic group, 3 - 12 membered heteroepoxy group, C 6-10 Aryl, C 6-10 Aryloxy, 5 - 10 membered heteroaryl, 5 - 10 membered heteroaryloxy and -NR 15 R 16 is substituted by a substituent of;

[0018] Each R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halo - substituted C 1-10 alkyl, deuterium - substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 - 12 membered heterocyclic group, C 6-10 aryl, 5 - 10 membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O - C(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 to which they are directly attached form a C 3-12 cycloalkyl or 3 - 12 membered heterocyclic group, and the above - mentioned groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo - substituted C 1-10 alkyl, deuterium - substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3 - 12 membered heterocyclic group, 3 - 12 membered heteroepoxy group, C 6-10 aryl, C 6-10 aryloxy, 5 - 10 membered heteroaryl, 5 - 10 membered heteroaryloxy and -NR 15 R 16 is substituted by a substituent of;

[0019] Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0020] R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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(R15 )-C(O)R 14 ;

[0021] Each R 12 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and -NR 15 R 16 , and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, and -NR 15 R 16 ;

[0022] Each R 13 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, and -NR 15 R 16 ;

[0023] Each R 14 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl, C 6-10Aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, and -NR 15 R 16 , where the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, and -NR 15 R 16 ;

[0024] Each R 15 and R 16 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, sulfinyl, sulfonyl, mesyl, isopropylsulfonyl, cyclopropylsulfonyl, tosyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino, and C 1-10 alkanoyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino, and C 1-10 alkanoyl;

[0025] Alternatively, R 15 and R 16 together with the nitrogen atom to which they are directly attached form a 4- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heteroepoxy group, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 substituted by a substituent of alkanoyl;

[0026] m is 0, 1 or 2;

[0027] each r is independently 0, 1 or 2.

[0028] As a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15 )-C(=NR 16 )R 14 、-C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 or, when m≥1, R1 and the adjacent R9 together with the part directly connected thereto form C 5-6 Cycloalkyl or 5-6 membered heterocyclic group;

[0029] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, 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 and 5-8 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15)-C(=NR 16 )R 14 、-C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 substituted by a substituent;

[0030] R4 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 substituted by a substituent;

[0031] R5 is selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group;

[0032] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted 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, 5-8 membered heteroaryl, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15 )-C(=NR 16 )R14 、 -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;

[0033] Alternatively, R5 and the moiety directly connected thereto together form a 4- to 6-membered heterocyclic group, and the above-mentioned 4- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0034] R7 and R8 are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, or R7 and the nitrogen atom directly connected thereto together form a 3- to 6-membered heterocyclic group, and the above-mentioned groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8Aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 15 R 16 is substituted by a substituent;

[0035] Each R9 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 R9s together with the moiety to which they are directly attached form a C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 15 R 16 is substituted by a substituent;

[0036] Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen-substituted C 1-4Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 Aryl, 5- to 8-membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0037] R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0038] wherein, R 12 , R 13 , R14 , R 15 , R 16 and r are as described in the compound of formula (I).

[0039] As a preferred embodiment, among the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, the compound of formula (I) is a compound of formula (IIa) as follows:

[0040]

[0041] Wherein, Z is CR 11 or N; Q is CH or N;

[0042] R1 is selected from hydrogen, chlorine, bromine and C 1-4 alkyl, and the C 1-4 alkyl is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, amino, dimethylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclic group;

[0043] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, or, R2 and R3 together with the carbon atom directly connected to them form C 3-6 cycloalkyl or 3-6 membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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(R15 )-C(O)R 14 is substituted by a substituent of;

[0044] R4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 is substituted by a substituent of;

[0045] R5 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 2-4 alkenyl;

[0046] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl and 5- to 8-membered heteroaryl;

[0047] R7 and R8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl and C 2-4 alkenyl, or R7 and R8 together with the nitrogen atom to which they are directly attached form a 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR15 R 16 is substituted by the substituents of;

[0048] R 9a is selected from 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 and C 6-8 aryl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 is substituted by the substituents of;

[0049] R 11 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group;

[0050] wherein, R 12 , R 13 , R 14 , R 15 , R 16 and r are as described for the compound of formula (I).

[0051] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of formula (IIIa1) as follows:

[0052]

[0053] wherein, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6A cycloalkyl group and a 3- to 6-membered heterocyclic group, or R2 and R3 together with the carbon atom directly attached thereto form a C 3-6 cycloalkyl group or a 3- to 6-membered heterocyclic group;

[0054] R4 is selected from hydrogen, deuterium, C 1-4 alkyl group and C 3-6 cycloalkyl group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3- to 6-membered heterocyclic group and 3- to 6-membered heterocyclic oxy group;

[0055] R5, R7 and R8 are each independently hydrogen or methyl;

[0056] R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 3- to 6-membered heterocyclic group and C 6-8 aryl group, and the above groups are optionally further substituted by one or more substituents selected from 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 group, C 3-6 cycloalkoxy group, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5- to 8-membered heteroaryl group, 5- to 8-membered heteroaryloxy group and -NR 15 R 16 ;

[0057] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or R2 and R3 together with the carbon atom directly connected thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or pyrrolidinyl, and the above cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or pyrrolidinyl is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl and cyclobutyl;

[0058] R4 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;

[0059] R5, R7 and R8 are each independently hydrogen or methyl;

[0060] R 9a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl and phenyl, and the phenyl is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0061] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of formula (IIIa2) as follows:

[0062]

[0063] wherein, R4 is selected from isopropyl and cyclopropyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0064] As a further preferred embodiment, among the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts, the compound of formula (I) is a compound of formula (IIIa3) as follows:

[0065]

[0066] Wherein, R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R2 and R3 together with the carbon atom directly connected thereto form cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or azolanyl, and the above cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or azolanyl are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl and cyclobutyl;

[0067] R4 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;

[0068] R5, R7 and R8 are each independently hydrogen or methyl;

[0069] R 9a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl and cyclobutyl,

[0070] provided that when R 9a is hydrogen, R2 and R3 together with the carbon atom directly connected thereto form cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or azolanyl.

[0071] As a further preferred embodiment, among the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts, the compound of formula (I) is a compound of formula (IIIa4) as follows:

[0072]

[0073] Wherein, R1 is chlorine or bromine;

[0074] R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or R2 and R3 together with the carbon atom directly attached thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or azolanyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolanyl or azolanyl is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl and cyclobutyl;

[0075] R4 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;

[0076] R5, R7 and R8 are each independently hydrogen or methyl;

[0077] R 9a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl and phenyl, and the phenyl is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0078] As a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of formula (IIb) as follows:

[0079]

[0080] wherein, one of X and Y is CH and the other is N; Z is CR 11 or N; Q is CH or N;

[0081] R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8Aryl, 5- to 8-membered heteroaryl, and -SF5, wherein the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0082] Alternatively, R1 and R 9a together with the moiety directly attached thereto form a C 5-6 cycloalkyl or 5- to 6-membered heterocyclic group;

[0083] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, or R2 and R3 together with the carbon atom directly attached thereto form a C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted by substituents of;

[0084] R4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 substituted by substituents of;

[0085] R5 is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 2-4 alkenyl;

[0086] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl and 5- to 8-membered heteroaryl;

[0087] Alternatively, R5 and the moiety directly connected thereto together form a 4- to 6-membered heterocyclic group, and the above 4- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halo-substituted C 1-4Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 Aryl, 5- to 8-membered heteroaryl, ═O, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted by substituents of;

[0088] R7 and R8 are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl and C 2-4 alkenyl, or R7 and R8 together with the nitrogen atom to which they are directly attached form a 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 substituted by substituents of;

[0089] R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8Aryl and 5- to 8-membered heteroaryl, the above groups optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 ;

[0090] R 11 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group;

[0091] wherein, R 12 , R 13 , R 14 , R 15 , R 16 and r are as described for the compound of formula (I).

[0092] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of formula (IIIb1) or (IIIb2) as follows:

[0093]

[0094] wherein, one of X and Y is CH and the other is N; each Q is CH or N;

[0095] each R1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 5- to 8-membered heteroaryl, the above groups optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C3-6 substituted by substituents of cycloalkyl and 3- to 6-membered heterocyclic group

[0096] Or, R1 and R 9a together with the part directly connected thereto form a C 5-6 cycloalkyl or 5- to 6-membered heterocyclic group;

[0097] Each R2 and R3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group, or, R2 and R3 together with the carbon atom directly connected thereto form a C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 3-6 substituted by substituents of cycloalkyl;

[0098] Each R4 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 3-6 cycloalkyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group and substituents of 3- to 6-membered heterocyclic oxy group;

[0099] In the compound of formula (Ⅲb1), R5 is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl and deuterium-substituted C 1-4 alkyl;

[0100] Each R7 and R8 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R7 and R8 together with the nitrogen atom directly connected thereto form a 3- to 6-membered heterocyclic group;

[0101] Each R 9a is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and C 6-8 aryl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, and is substituted by substituents of a 3- to 6-membered heterocyclic group and a 3- to 6-membered heterocyclic oxy group.

[0102] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R1 is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;

[0103] or, R1 and R 9a together with the moiety directly attached thereto form cyclopentyl;

[0104] Each R2 and R3 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl, or, R2 and R3 together with the carbon atom directly attached thereto form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, and the above C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl and cyclobutyl;

[0105] Each R4 is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl;

[0106] In the compound of formula (Ⅲb1), R5 is selected from hydrogen, deuterium and methyl;

[0107] Each R7 and R8 are independently selected from hydrogen, deuterium and methyl;

[0108] Each R 9aEach independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl and phenyl, said phenyl optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0109] As a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of formula (IIc) as follows:

[0110]

[0111] Wherein, Z is CR 11 or N; Q is CH or N;

[0112] R1 is selected from 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, 5-8 membered heteroaryl and -SF5, the above groups optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0113] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, or, R2 and R3 together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0114] R4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 ;

[0115] R5 is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, and C 2-4 alkenyl;

[0116] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, and 5- to 8-membered heteroaryl;

[0117] Alternatively, R5 and the moiety directly attached thereto together form a 4- to 6-membered heterocyclic group, and the above-mentioned 4- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, ═O, -SF5, -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 ;

[0118] R7 and R8 are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, and C 2-4 alkenyl, or R7 and R8 together with the nitrogen atom directly attached thereto form a 3- to 6-membered heterocyclic group, and the above-mentioned group is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 Aryl, C 6-8 Aryloxy, 5- to 8-membered heteroaryl group, 5- to 8-membered heteroaryloxy group, and -NR 15 R 16 is substituted by the substituents of;

[0119] R 11 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group;

[0120] wherein, R 12 , R 13 , R 14 , R 15 , R 16 and r are as described for the compound of formula (I).

[0121] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (IIIc1) or (IIIc2):

[0122]

[0123] wherein each Q is CH or N;

[0124] Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl and 5- to 8-membered heteroaryl group, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group;

[0125] Each R2 and R3 is independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C1-4 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclic group, or R2 and R3 together with the carbon atom directly connected thereto form C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group;

[0126] Each R4 is independently selected from hydrogen, deuterium, C 1-4 alkyl, and C 3-6 cycloalkyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, and 3- to 6-membered heterocyclic oxy group;

[0127] In the compound of formula (Ⅲc1), R5 is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl;

[0128] Each R7 and R8 is independently selected from hydrogen, deuterium, and C 1-4 alkyl, or R7 and R8 together with the nitrogen atom directly connected thereto form a 3- to 6-membered heterocyclic group.

[0129] As a further preferred embodiment, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, each R1 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl;

[0130] Each R2 and R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl;

[0131] Each R4 is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl;

[0132] In the compound of formula (Ⅲc1), R5 is selected from hydrogen, deuterium, and methyl;

[0133] Each of R7 and R8 is independently selected from hydrogen, deuterium and methyl.

[0134] As a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 12 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl and -NR 15 R 16 , and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 ;

[0135] Each R 13 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl and 5- to 8-membered heteroaryl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 ;

[0136] Each R 14 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 , where the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 15 R 16 ;

[0137] Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, where the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;

[0138] Alternatively, R 15 and R 16 together with the nitrogen atom to which they are directly attached form a 5- to 8-membered heterocyclic group or 5- to 8-membered heteroaryl, where the above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 substituted by a substituent of alkanoyl.

[0139] As a most preferred embodiment, the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts include, but are not limited to, the following compounds:

[0140]

[0141]

[0142]

[0143]

[0144] The second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, comprising the following steps:

[0145]

[0146] wherein X1 is a halogen, preferably selected from fluorine, chlorine and bromine; R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, Z, Q and m are as defined for the compound of formula (I).

[0147] The third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0148] The present invention also relates to the use of the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts in the preparation of a medicament for the treatment and / or prevention of at least partially cancers, tumors or metastatic diseases associated with EGFR exon 20 insertions, deletions or other mutations.

[0149] The present invention also relates to the use of a compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and disorders of induced cell death.

[0150] The present invention also relates to the use of the aforementioned compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and paranasal sinus inverted papillomas or nasal and paranasal sinus squamous cell carcinomas associated with nasal and paranasal sinus inverted papillomas, at least in part related to EGFR exon 20 insertions, deletions or other mutations.

[0151] The present invention also relates to the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, which is used as a medicament.

[0152] The present invention also relates to the use of the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof for treating and / or preventing cancers, tumors or metastatic diseases that are at least in part related to EGFR exon 20 insertions, deletions or other mutations.

[0153] The present invention also relates to the use of the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and disorders of induced cell death.

[0154] The present invention also relates to the use of the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof 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 tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and paranasal sinus inverted papillomas or nasal and paranasal sinus squamous cell carcinomas associated with nasal and paranasal sinus inverted papillomas, at least in part related to EGFR exon 20 insertions, deletions or other mutations.

[0155] The present invention also relates to a method for treating and / or preventing cancers, tumors or metastatic diseases that are at least in part related to EGFR exon 20 insertions, deletions or other mutations, which comprises administering to a patient in need a therapeutically effective amount of the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof.

[0156] The present invention also relates to a method for preventing and / or treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and disorders of induced cell death, which comprises administering to a patient in need a therapeutically effective amount of the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts.

[0157] 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 tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and paranasal sinus inverted papillomas or nasal and paranasal sinus squamous cell carcinomas associated with nasal and paranasal sinus inverted papillomas, which comprises administering to a patient in need a therapeutically effective amount of the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts. Detailed Description

[0158] Through extensive and in-depth research, the inventors of the present application have developed for the first time an EGFR inhibitor with the structure of formula (I). The series of compounds of the present invention can be widely used in the preparation of drugs for treating and / or preventing cancers, tumors or metastatic diseases that are at least partially related to EGFR exon 20 insertions, deletions or other mutations, especially drugs for treating hyperproliferative diseases and diseases of induced cell death disorders, and are expected to be developed into a new generation of EGFR inhibitors. On this basis, the present invention has been completed.

[0159] Detailed Explanation: Unless otherwise stated or specifically noted, the following terms used in the specification and claims have the following meanings.

[0160] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyl groups and branched alkyl groups having 1 to 10, or 1 to 6, or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C 1-10 "alkyl" refers to straight-chain alkyl groups and branched alkyl groups having 1 to 10 carbon atoms, "C 1-4 "alkyl" refers to straight-chain alkyl groups and branched alkyl groups having 1 to 4 carbon atoms.

[0161] The alkyl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, -SF5, -S(O) r R 12 、-O-R 13 、-C(O)OR 13 、-C(O)R 14 、-O-C(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15 )-C(=NR16 )R 14 、 -C(O)NR 15 R 16 or -N(R 15 )-C(O)R 14 and is substituted by a substituent of.

[0162] "Cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system. Cycloalkyl is divided into monocyclic cycloalkyl and polycyclic cycloalkyl, preferably including cycloalkyl having 3 to 12 or 3 to 8 or 3 to 6 carbon atoms. For example, " 3-12 cycloalkyl" refers to cycloalkyl having 3 to 12 carbon atoms, " 3-6 cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, wherein:

[0163] Monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0164] Polycyclic cycloalkyl includes spiro, fused - ring and bridged - ring cycloalkyl. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between monocyclic rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system. Spirocycloalkyl is divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl according to the number of spiro atoms shared between rings. Spirocycloalkyl includes but is not limited to:

[0165]

[0166] "Fused - ring cycloalkyl" refers to a fully carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused - ring cycloalkyl according to the number of constituent rings. Fused - ring cycloalkyl includes but is not limited to:

[0167]

[0168] "Bridged - ring cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non - directly - connected carbon atoms. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged - ring cycloalkyl according to the number of constituent rings. Bridged - ring cycloalkyl includes but is not limited to:

[0169]

[0170] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0171] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15 )-C(=NR 16 )R 14 、-C(O)NR 15 R 16 or -N(R 15 )-C(O)R 14 substituted by a substituent.

[0172] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r(where r is an integer 0, 1, 2) heteroatoms, but excluding the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. A heterocyclic group preferably includes 3 to 12 or 3 to 8 or 3 to 6 ring atoms. For example, "3-6 membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, "4-6 membered heterocyclic group" refers to a ring group containing 4 to 6 ring atoms, "4-10 membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, and "3-12 membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms.

[0173] Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, etc.

[0174] Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between monocyclic rings, and one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings has a completely conjugated π - electron system. Spiropolycyclic heterocyclic groups are classified into monospiro heterocyclic groups, dispiro heterocyclic groups or polyspiro heterocyclic groups according to the number of spiro atoms shared between rings. Spiropolycyclic heterocyclic groups include but are not limited to:

[0175]

[0176] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include but are not limited to:

[0177]

[0178] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non - directly - connected atoms. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π - electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r(wherein r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and the bridged heterocyclic groups include but are not limited to:

[0179]

[0180] The heterocyclic group ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0181]

[0182] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted.

[0183] "Aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic group with a conjugated π-electron system (i.e., the rings thereof with adjacent pairs of carbon atoms), preferably a fully carbon aryl containing 5-10 or 5-8 carbons. For example, "C 6-10 aryl" refers to a fully carbon aryl containing 6-10 carbons, including but not limited to phenyl and naphthyl, "C 6-8"Aryl" refers to a fully carbon aryl group containing 6 - 8 carbons, and the aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring, including but not limited to:

[0184]

[0185] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo - substituted C 1-10 alkyl, deuterium - substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3 - 12 - membered heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, ═O, - SF5, - S(O) r R 12 、- O - R 13 、- C(O)OR 13 、- C(O)R 14 、- O - C(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 and is substituted by the substituents.

[0186] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O) r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5 - 10 or 5 - 8 or 5 - 6 ring atoms. For example, 5 - 6 - membered heteroaryl refers to a heteroaromatic system containing 5 - 6 ring atoms, 5 - 8 - membered heteroaryl refers to a heteroaromatic system containing 5 - 8 ring atoms, and 5 - 10 - membered heteroaryl refers to a heteroaromatic system containing 5 - 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N - alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring, including but not limited to:

[0187]

[0188] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted by substituents of.

[0189] "Alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight-chain or branched-chain alkenyl group containing 2-10 or 2-4 carbons. For example, C 2-10 Alkenyl refers to a straight-chain or branched-chain alkenyl group containing 2-10 carbons, C 2-4 Alkenyl refers to a straight-chain or branched-chain alkenyl group containing 2-4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0190] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12Cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, ═O, -SF5, -S(O) r R 12 、-O-R 13 、-C(O)OR 13 、-C(O)R 14 、-O-C(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 and is substituted by a substituent thereof.

[0191] "Alkynyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched alkynyl group containing 2-10 or 2-4 carbons. For example, C 2-10 Alkynyl refers to a straight-chain or branched alkynyl group containing 2-10 carbons, C 2-4 Alkynyl refers to a straight-chain or branched alkynyl group containing 2-4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0192] "Alkynyl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, ═O, -SF5, -S(O) r R 12 、-O-R 13 、-C(O)OR 13 、-C(O)R 14 、-O-C(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 substituted by a substituent.

[0193] "Alkoxy" refers to an -O-alkyl group in which alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, C 1-4 The term "alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

[0194] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R 12 、-OR 13 、-C(O)OR 13 、-C(O)R 14 、-OC(O)R 14 、-NR 15 R 16 、-C(=NR 15 )R 14 、-N(R 15 )-C(=NR 16 )R 14 、-C(O)NR 15 R 16 or -N(R 15 )-C(O)R 14 substituted by a substituent.

[0195] "Cycloalkoxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkyloxy" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms. 3-6 The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 6 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0196] "Cyclanoxy" can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted by the substituents of.

[0197] "Heteroepoxy" means -O-heterocyclic group, where the heterocyclic group is defined as above, including but not limited to azetidyloxy, oxetidyloxy, pyrrolidinyloxy, morpholino, etc.

[0198] "Heteroepoxy" can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, -SF5, -S(O) r R 12 , -O-R 13 , -C(O)OR 13 , -C(O)R 14 , -O-C(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 substituted by a substituent.

[0199] “C 1-10 "Alkanoyl" refers to C 1-10 The monovalent atomic group remaining after removing the hydroxyl group from the alkyl acid is usually expressed as "C 0-9 "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionyl; "C3 alkyl-C(O)-" refers to butyryl or isobutyryl.

[0200] "Halogen-substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0201] "Halogen-substituted C 1-10 The term "alkoxy" refers to an alkoxy group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms. It includes, but is not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

[0202] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0203] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0204] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

[0205] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in line with the chemical valence bond theory, and those skilled in the art can determine (through experiments or theory) what substitutions are possible or impossible without much effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0206] "Stereoisomer", whose English name is stereoisomer, refers to isomers generated by different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or it can be divided into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by reasons such as bond length, bond angle, the presence of double bonds or rings in the molecule are called configuration stereo-isomers, and configuration stereo-isomers are further divided into two types. Among them, isomers caused by the inability of double bonds or single bonds of ring-forming carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule are called optical isomers, and are divided into two configurations: R and S. In the present invention, the "stereoisomer" mentioned, unless otherwise specified, can be understood to include one or several of the above-mentioned enantiomers, configuration isomers and conformational isomers.

[0207] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, and these salts can be prepared by methods known in the art.

[0208] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0209] The present invention will be further described in detail and completely below in conjunction with the embodiments, but it is by no means a limitation of the present invention, and the present invention is not only limited to the content of the embodiments.

[0210] The structure of the compounds of the present invention was determined by nuclear magnetic resonance (NMR) or / and liquid chromatography - mass spectrometry (LC - MS). NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurements were carried out using a Bruker AVANCE - 400 / 500 nuclear magnetic resonance spectrometer. The solvents for the measurements were deuterated dimethyl sulfoxide (DMSO - d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0211] The LC - MS measurements were carried out using an Agilent 6120 mass spectrometer. The HPLC measurements were carried out using an Agilent 1200 DAD high - pressure liquid chromatography instrument (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695 - 2996 high - pressure liquid chromatography instrument (Gimini C18 150×4.6 mm chromatographic column).

[0212] The thin - layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications for TLC were 0.15 mm - 0.20 mm, and the specifications for the separation and purification of products by thin - layer chromatography were 0.4 mm - 0.5 mm. Column chromatography generally used Yantai Huanghai silica gel with 200 - 300 mesh as the carrier.

[0213] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized by methods known in the art or according to the methods known in the art.

[0214] Unless otherwise specified, all reactions of the present invention were carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with the solvent being a dry solvent, and the reaction temperature unit being degrees Celsius (°C).

[0215] I. Preparation of intermediates

[0216] Preparation of Intermediate A1: 3,3 - dimethyl - 2,3 - dihydro - 1H - pyrrolo[3,2 - b]pyridine

[0217]

[0218] First step: Synthesis of 2 - iodo - N - (2 - methylallyl)pyridin - 3 - amine

[0219]

[0220] At room temperature, a solution of potassium tert-butoxide in tetrahydrofuran (27 mL, 1 M, 27.2 mmol) was added to a solution of 2-iodopyridin-3-amine (5 g, 22.7 mmol) in tetrahydrofuran (100 mL). 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 solvent was removed by concentration under reduced pressure. The residue was separated by flash silica gel column chromatography [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] + 。

[0221] Step 2: Synthesis of 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0222]

[0223] 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), dimethyl sulfoxide (50 mL) and water (3 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and then heated to 120 °C and stirred for 1 hour under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, the crude product was separated by flash silica gel column chromatography [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] + 。

[0224] Intermediate A2: Preparation of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0225]

[0226] Step 1: Synthesis of 6-chloro-2-iodopyridin-3-amine

[0227]

[0228] To a solution of 6-chloropyridin-3-amine (12.1 g, 94.1 mmol) in N,N-dimethylformamide (200 mL) was added N-iodosuccinimide (23.3 g, 103.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [petroleum ether: ethyl acetate = 4:1] to give 6-chloro-2-iodopyridin-3-amine (17.4 g, yield: 72.65%). ESI-MS: 254.8 [M+1] + 。

[0229] 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).

[0230] Step 2: Synthesis of 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine

[0231]

[0232] To a solution of 6-chloro-2-iodopyridin-3-amine (17.4 g, 68.3 mmol) in tetrahydrofuran (200 mL) were added 3-bromo-2-methylprop-1-ene (11.0 g, 82.0 mmol) and a solution of potassium tert-butoxide in tetrahydrofuran (82.0 mL, 1 M, 82.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [petroleum ether: ethyl acetate = 4:1] to give 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine (19.4 g, yield: 91.9%). ESI-MS: 308.8 [M+1] + 。

[0233] Step 3: Synthesis of 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0234]

[0235] To a solution of 6-chloro-2-iodo-N-(2-methylallyl)pyridin-3-amine (15.5 g, 50.2 mmol) in dimethyl sulfoxide / water (200 mL / 6 mL) were added 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(II) acetate (1.7 g, 7.5 mmol). After evacuation and replacement with nitrogen, the reaction mixture was stirred at 120 °C for 2 h. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [petroleum ether:ethyl acetate = 4:1] to give 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] + 。

[0236] Intermediate A3: Preparation of 3,3,5-Trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0237]

[0238] 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) were added methylboronic acid (10.7 g, 178.7 mmol), potassium phosphate (22.6 g, 106.7 mmol), tricyclohexylphosphine (3.0 g, 10.6 mmol) and palladium(II) acetate (1.2 g, 5.3 mmol). After evacuation and replacement with nitrogen, the reaction mixture was stirred at 110 °C for 18 h. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [petroleum ether:ethyl acetate = 3:1] to give 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] + 。

[0239] Intermediate A4: Preparation of 5-Cyclopropyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0240]

[0241] Add 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (450 mg, 2.5 mmol), cyclopropylboronic acid (1.1 g, 12.4 mmol), potassium phosphate (1.94 g, 9.1 mmol), tricyclohexylphosphine (138 mg, 0.5 mmol), palladium acetate (55 mg, 0.3 mmol), and toluene (30 mL) to a reaction flask. The mixture is purged with nitrogen three times and then heated to 110 °C and stirred for 6 hours under nitrogen protection. The reaction solution is filtered, the filtrate is washed with water, extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product is separated by flash silica gel column chromatography [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] + 。

[0242] Intermediate A5: Preparation of 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0243]

[0244] Add 5-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (274 mg, 1.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) to a reaction flask. The mixture is purged with nitrogen three times and then heated to 110 °C and stirred for 16 hours under nitrogen protection. The reaction solution is filtered, the filtrate is washed with water, extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product is separated by flash silica gel column chromatography [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] + 。

[0245] Intermediate A6: Preparation of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0246]

[0247] Step 1: Synthesis of 6-bromo-2-iodopyridin-3-amine

[0248]

[0249] To a solution of 6-bromopyridin-3-amine (1.73 g, 10 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added N-iodosuccinimide (2.70 g, 12.0 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by flash silica gel column chromatography [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] + 。

[0250] Step 2: Synthesis of 6-bromo-2-iodo-N-(2-methylallyl)pyridin-3-amine

[0251]

[0252] To a solution of 6-bromo-2-iodopyridin-3-amine (2.09 g, 7.0 mmol) in tetrahydrofuran (50 mL) at room temperature was added potassium tert-butoxide (8.4 mL, 8.4 mmol, 1 M / mL). The mixture was stirred at room temperature for 15 minutes. Then 3-bromo-2-methylprop-1-ene (1.04 g, 7.7 mmol) was slowly added dropwise to the mixture. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated by flash silica gel column chromatography [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] + 。

[0253] Step 3: Synthesis of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0254]

[0255] Add 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), dimethyl sulfoxide (20 mL) and water (2 mL) to a reaction flask. The mixture is purged with nitrogen three times. Under nitrogen protection, it is heated to 120 °C and stirred for 1 hour. The reaction solution is filtered, the filtrate is washed with water, extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product is separated by 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] + 。

[0256] Intermediate A7: Preparation of 5-(1H-imidazol-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0257]

[0258] Add 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(I) 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) to a reaction flask. The mixture is purged with nitrogen three times. Under nitrogen protection, it is heated to 110 °C and stirred for 16 hours. The reaction solution is filtered, the filtrate is washed with water, extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product is separated by 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] + 。

[0259] Intermediate A8: Preparation of 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0260]

[0261] Step 1: Synthesis of 6-chloro-2-iodo-5-methylpyridin-3-amine

[0262]

[0263] To a solution of 6-chloro-5-methylpyridin-3-amine (5.0 g, 35.1 mmol) in N,N-dimethylformamide (100 mL) was added N-iodosuccinimide (10.2 g, 45.6 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, concentrated, and purified by column chromatography [petroleum ether:ethyl acetate = 4:1] to give 6-chloro-2-iodo-5-methylpyridin-3-amine (8.18 g, yield: 78.2%). ESI-MS: 269.0 [M+1] + 。

[0264] Step 2: Synthesis of 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine

[0265]

[0266] To a solution of 6-chloro-2-iodo-5-methylpyridin-3-amine (5.5 g, 20.5 mmol) in tetrahydrofuran (50 mL) were added 3-bromo-2-methylprop-1-ene (3.32 g, 24.6 mmol) and a solution of potassium tert-butoxide in tetrahydrofuran (24.6 mL, 1 M, 24.6 mmol). The reaction was stirred at room temperature for 20 min. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, concentrated, and purified by column chromatography [petroleum ether:ethyl acetate = 4:1] to give 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine (3.55 g, yield: 53%). ESI-MS: 323.0 [M+1] + 。

[0267] Step 3: Synthesis of 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0268]

[0269] To a solution of 6-chloro-2-iodo-5-methyl-N-(2-methylallyl)pyridin-3-amine (3.35 g, 10.4 mmol) in dimethyl sulfoxide / water (60 mL / 2.6 mL) were added 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(II) acetate (0.35 g, 1.5 mmol). After evacuation and replacement with nitrogen, the reaction mixture was stirred at 120 °C for 2 h. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [petroleum ether:ethyl acetate = 4:1] to give 5-chloro-3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.5 g, yield: 67.2%). ESI-MS: 197.0 [M+1] + 。

[0270] Intermediate A9: Preparation of 3,3,5,6-tetramethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0271]

[0272] 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) were added trimethylcyclotriboroxane (3.5 mL, 3.5 M, 12.3 mmol), potassium carbonate (1.02 g, 7.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (199 mg, 0.24 mmol). After evacuation and replacement with nitrogen, the reaction mixture was stirred at 120 °C for 1 h. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated and separated by column chromatography [dichloromethane:methanol = 5:1] to give 3,3,5,6-tetramethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (376 mg, yield: 77.80%). ESI-MS: 177.0 [M+1] + 。

[0273] Intermediate A10: Preparation of 3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0274]

[0275] First step: Synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate

[0276]

[0277] Dissolve 5-bromo-2-chloro-3-nitropyridine (2.5 g, 10.53 mmol) in acetonitrile (50 mL). Add potassium 3-ethoxy-3-oxopropionate (2.15 g, 12.64 mmol), magnesium chloride (1.5 g, 15.79 mmol) and triethylamine (2.93 mL, 21.06 mmol). The reaction is stirred at 70 °C for 16 h. The reaction solution is adjusted to pH = 7 with 1N hydrochloric acid, extracted with dichloromethane (100 mL), and the organic phase is washed successively with water (50 mL) and saturated brine (50 mL). The organic phase is concentrated, and the residue is separated by flash silica gel column [petroleum ether: ethyl acetate = 3:1] to obtain ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (890 mg, yield: 29%). ESI-MS: 289.0, 290.9 [M+1] + 。

[0278] Step 2: Synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropionate

[0279]

[0280] Dissolve ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (710 mg, 2.46 mmol) in tetrahydrofuran (50 mL). Add 18-crown-6 (64.9 mg, 0.25 mmol), methyl iodide (0.46 mL, 7.37 mmol) and sodium hydride (177 mg, 7.37 mmol) to the reaction solution. The reaction solution is stirred at 0 °C under nitrogen protection for 3 h. After the reaction is completed, the reaction solution is separated with ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase is washed with saturated brine (50 mL). The obtained organic phase is concentrated, and the residue is passed through a flash silica gel column [petroleum ether / ethyl acetate = 3 / 1] to obtain ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropionate (532 mg, yield: 68%). ESI-MS: 317.0, 319.0 [M+1] + 。

[0281] Step 3: Synthesis of 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0282]

[0283] 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 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting residue was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was concentrated, and the residue was separated by flash silica gel column chromatography [petroleum ether / ethyl acetate = 2 / 1] to give 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] + 。

[0284] Step 4: Synthesis of 3,3,6-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0285]

[0286] 6-Bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (140 mg, 0.58 mmol), trimethylboroxine (108 mg, 0.87 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (42 mg, 0.058 mmol) and potassium carbonate (161 mg, 1.16 mmol) were dissolved in dimethoxyethylene glycol (5 mL). The reaction mixture was stirred at 90 °C for 1 h under nitrogen protection until the reaction was completed. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated, and the residue was separated by flash silica gel column chromatography [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] + 。

[0287] Step 5: Synthesis of 3,3,6-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0288]

[0289] Dissolve 3,3,6-trimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (85 mg, 0.48 mmol) in tetrahydrofuran (20 mL). Add borane tetrahydrofuran solution (1.4 mL, 1.4 mmol) to the reaction solution. Stir the reaction solution at 70 °C for 16 hours under nitrogen protection to complete the reaction. The reaction solution is separated with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase is washed with saturated brine (50 mL). The obtained organic phase is concentrated, and the residue is separated by flash silica gel column chromatography [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] + .

[0290] Intermediates A11 to A12 were prepared by referring to the preparation method of Intermediate A10:

[0291]

[0292] Preparation of Intermediate A13: 5'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0293]

[0294] First step: Synthesis of diethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate

[0295]

[0296] Slowly drop diethyl malonate (11.14 g, 69.54 mmol) into a suspension of sodium hydride (3.01 g, 75.33 mmol) in dimethyl sulfoxide (140 mL) at 0 °C. Stir the mixture at room temperature for 0.5 hour, and then add 2-chloro-6-methyl-3-nitropyridine (10 g, 57.95 mmol) to the mixture. Stir the reaction solution at 100 °C for 1.5 hours. After the reaction is completed, cool it to 0 °C, and slowly add saturated sodium bicarbonate to quench the reaction. Wash the mixture with water, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, and distill under reduced pressure. The crude product is 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] + .

[0297] Second step: Synthesis of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate

[0298]

[0299] To a solution of diethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate (8.66 g, 26.60 mmol) in dimethyl sulfoxide (65 mL) was added water (10 mL) and lithium chloride (2.74 mL, 132.99 mmol). 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, distilled under reduced pressure, and 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] + 。

[0300] Step 3: Synthesis of ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate

[0301]

[0302] Under nitrogen protection at room temperature, to a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (180 mg, 0.80 mmol) in dimethyl sulfoxide (10 mL) was added diphenyl(vinyl)sulfonium trifluoromethanesulfonate (565 mg, 1.56 mmol). The mixture was stirred at room temperature for 10 minutes, then dry 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.36 mL, 2.41 mmol) was added. After the reaction was completed, it 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 analyzed 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] + 。

[0303] Step 4: Synthesis of 5'-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0304]

[0305] To a solution of ethyl 1-(6-methyl-3-nitropyridin-2-yl)cyclopropane-1-carboxylate (144 mg, 0.55 mmol) in ethanol (20 mL) was added ammonium formate (0.14 mL, 2.73 mmol) and 10% palladium on carbon (20 mg). The mixture was stirred at 90 °C for 18 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated. The residue was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, crude 5'-methylspiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (80 mg, yield: 77.29%) was obtained and directly used in the next step. ESI-MS: 175.0 [M+1] + 。

[0306] Step 5: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0307]

[0308] 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). The solution was cooled to 0 °C, and a solution of lithium aluminum hydride in tetrahydrofuran (0.83 mL, 2.07 mmol) was added dropwise to the solution. The mixture was stirred at 50 °C for 3 h. After completion of the reaction, the reaction mixture 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 5'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (64 mg, yield: 78.28%). ESI-MS: 161.0 [M+1] + 。

[0309] Intermediate A14: Preparation of 5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]

[0310]

[0311] Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 2-(6-methyl-3-nitropyridin-2-yl)malonate

[0312]

[0313] At 0 °C, 1-tert-butyl 3-ethyl malonate (35.45 g, 188.3 mmol) was slowly added dropwise to a suspension of sodium hydride (6.95 g, 173.8 mmol) in tetrahydrofuran (200 mL). The mixture was stirred in an ice bath for 0.5 h, and then 2-chloro-6-methyl-3-nitropyridine (25 g, 144.8 mmol) was added to the mixture. The reaction solution was stirred at 60 °C for 18 h. 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, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, the crude product was separated by flash silica gel column chromatography [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] + 。

[0314] Step 2: Synthesis of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate

[0315]

[0316] 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). The mixture was stirred at 60 °C for 2 h. The reaction solution was distilled under reduced pressure, and the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 15%] to obtain ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (22 g, yield: 89%). ESI-MS: 225.0 [M+1] + 。

[0317] Step 3: Synthesis of ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate

[0318]

[0319] 10% palladium on carbon (3.0 g) was added to a solution of ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate (22 g, 95.4 mmol) in methanol (150 mL). The mixture was stirred under hydrogen at room temperature overnight. 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] + 。

[0320] Step 4: Synthesis of 5-Methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0321]

[0322] Ethyl 2-(3-amino-6-methylpyridin-2-yl)acetate (17.5 g, 78.4 mmol) was added to a solution of hydrochloric acid (1 M) (100 mL). The mixture was stirred at 55 °C for 5 h. After completion of the reaction, the mixture was adjusted to alkaline with saturated sodium bicarbonate and extracted with dichloromethane:methanol = 10:1 solvent for several times. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure. The crude product was separated by 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] + 。

[0323] Step 5: Synthesis of 5'-Methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0324]

[0325] Sodium hydride (674.9 mg, 16.8 mmol) was dissolved in N,N-dimethylformamide (20 mL) and hexamethylphosphoric triamide (2 mL), and cooled to 0 °C. A solution of 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.0 g, 6.7 mmol) and 1,3-diiodopropane (0.78 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to the solution. The mixture was stirred at 0 °C for 1 h. 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 and distilled under reduced pressure. The crude product was separated by flash silica gel column [eluent: petroleum ether / ethyl acetate: 0 - 30%] to obtain 5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (260 mg, yield: 20%). ESI-MS: 189.0 [M+1] + 。

[0326] Step 6: Synthesis of 5'-Methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine

[0327]

[0328] Dissolve 5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (263 mg, 1.4 mmol) in tetrahydrofuran (20 mL), cool to 0 °C, and add dropwise a solution of lithium aluminum hydride in tetrahydrofuran (1.7 mL, 2.5 M) to the solution. The mixture was stirred at 50 °C for 2 hours. After the reaction was completed, 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 5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine] (260 mg, yield: 76%). ESI-MS: 175.0 [M+1] + 。

[0329] Intermediate A15: Preparation of 5'-methyl-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]

[0330]

[0331] First step: Synthesis of 5'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0332]

[0333] Dissolve 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (800 mg, 5.4 mmol) in anhydrous tetrahydrofuran (40 mL) and hexamethylphosphoramide (4.7 mL), cool to -78 °C, and slowly add dropwise a solution of n-butyllithium in tetrahydrofuran (6.5 mL, 16.2 mmol) 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 the reaction was completed, the reaction solution was poured into ice 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 [eluent: petroleum ether / ethyl acetate: 0 - 30%] to obtain 5'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (450 mg, yield: 41%). ESI-MS: 203.0 [M+1] + 。

[0334] Second step: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]

[0335]

[0336] Dissolve 5'-methylspiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (545 mg, 2.7 mmol) in tetrahydrofuran (20 mL), cool to 0 °C, and add dropwise a solution of lithium aluminum hydride in tetrahydrofuran (1.7 mL, 2.5 M) to the solution. The mixture was stirred at 50 °C for 2 h. 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 5'-methyl-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine] (465 mg, yield: 83%). ESI-MS: 189.0 [M+1] + 。

[0337] Intermediate A16: Preparation of 5'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]

[0338]

[0339] First step: Synthesis of 5'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0340]

[0341] Dissolve 5-methyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (200 mg, 1.35 mmol) in anhydrous tetrahydrofuran (15 mL) and hexamethylphosphoric triamide (1.5 mL), cool to -78 °C, and slowly add dropwise a solution of n-butyllithium in tetrahydrofuran (1.89 mL, 4.73 mmol) to the solution. The reaction solution was stirred for 30 min, and 1,5-diiodopentane (0.60 mL, 4.05 mmol) was added dropwise. The mixture was stirred at -20 °C for 1 h. 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 and distilled under reduced pressure. The crude product was separated by flash silica gel column [eluent: petroleum ether / ethyl acetate: 0 - 30%] to obtain 5'-methylspiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (220 mg, yield: 75.36%). ESI-MS: 217.0 [M+1] + 。

[0342] Second step: Synthesis of 5'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine]

[0343]

[0344] 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), cooled to 0 °C, and a solution of lithium aluminum hydride 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 the reaction was completed, 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 5'-methyl-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[3,2-b]pyridine] (190 mg, yield: 92.2%). ESI-MS: 203.0 [M+1] + 。

[0345] Intermediate A17: Preparation of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]

[0346]

[0347] First step: Synthesis of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'-one

[0348]

[0349] 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 hexamethylphosphoramide (5 mL), cooled to -78 °C, and a solution of n-butyllithium in tetrahydrofuran (3.65 mL, 9.11 mmol) was slowly added dropwise to the solution. The reaction solution 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 the reaction was completed, the reaction solution was poured into ice 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: petroleum ether / ethyl acetate: 0 - 30%] to obtain 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'-one (191 mg, yield: 28.81%). ESI-MS: 219.3 [M+1] + 。

[0350] Second step: Synthesis of 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]

[0351]

[0352] Dissolve 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'-one (191 mg, 0.88 mmol) in tetrahydrofuran (8 mL), cool to 0 °C, and add dropwise a solution of lithium aluminum hydride in tetrahydrofuran (0.88 mL, 2.5 M) to the solution. The mixture was stirred at 50 °C for 2 h. 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 5'-methyl-2,3,5,6-tetrahydro-2'H-1'l2-spiro[pyran-4,3'-pyrrolo[3,2-b]pyridine] (175 mg, yield: 97.9%). ESI-MS: 205.2 [M+1] + 。

[0353] Intermediate A18: Preparation of 1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]

[0354]

[0355] First step: Synthesis of 1-(tert-butyl) 3-ethyl 2-(3-nitropyridin-2-yl) malonate

[0356]

[0357] At 0 °C, tert-butyl ethyl malonate (44.52 g, 236.5 mmol) was slowly added dropwise to a suspension of sodium hydride (9.46 g, 236.5 mmol) in tetrahydrofuran (200 mL). The mixture was stirred at room temperature for 0.5 h, and then 2-chloro-3-nitropyridine (25.0 g, 157.7 mmol) was added to the mixture. The reaction solution was stirred at 60 °C for 1.5 h. After completion of the reaction, it was cooled to 0 °C, and saturated ammonium chloride solution was slowly added to quench the reaction. The mixture was washed with water, 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 [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] + 。

[0358] Second step: Synthesis of ethyl 2-(3-nitropyridin-2-yl) acetate

[0359]

[0360] To 1-(tert-butyl)-3-ethyl 2-(3-nitropyridin-2-yl)malonate (32.7 g, 84.3 mmol) was added 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 trifluoroacetic acid was removed by distillation under reduced pressure. The residue was added to saturated sodium bicarbonate solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and ethyl 2-(3-nitropyridin-2-yl)acetate (17.7 g, yield: 91.9%) was obtained after distillation under reduced pressure. ESI-MS: 211.0 [M+1] + 。

[0361] Step 3: Synthesis of ethyl 2-(3-aminopyridin-2-yl)acetate

[0362]

[0363] 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 under hydrogen at room temperature overnight. 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] + 。

[0364] Step 4: Synthesis of 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0365]

[0366] Ethyl 2-(3-aminopyridin-2-yl)acetate (17.5 g, 96.6 mmol) was added to a solution of hydrochloric acid (1 M) (100 mL). The mixture was stirred at 55 °C for 5 hours. After the reaction was completed, it was adjusted to alkaline with saturated sodium bicarbonate and extracted multiple times with a solvent of dichloromethane:methanol = 10:1. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by 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] + 。

[0367] Step 5: Synthesis of spiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0368]

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

[0370] Step 6: Synthesis of 1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]

[0371]

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

[0373] Intermediate A19: Preparation of 3,3-difluoro-5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]

[0374]

[0375] Step 1: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluorocyclobutane-1-carboxamide

[0376]

[0377] Dissolve 2-bromo-6-methylpyridin-3-amine (5 g, 26.732 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (4.37 g, 32.079 mmol), and 1-methylimidazole (6.58 g, 80.197 mmol) in acetonitrile (150 mL). Add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (9.00 g, 32.078 mmol). Stir the mixture at room temperature for 3 hours. After the reaction is completed, pour the reaction solution into water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate and distill under reduced pressure. Purify the crude product by flash silica gel column chromatography [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] + 。

[0378] Step 2: Synthesis of N-(2-bromo-6-methylpyridin-3-yl)-3,3-difluoro-N-(4-methoxybenzyl)cyclobutane-1-carboxamide

[0379]

[0380] Add 1-(chloromethyl)-4-methoxybenzene (2.01 mL, 14.75 mmol) and potassium carbonate (4.08 g, 29.50 mmol) 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). Stir the mixture at 90 °C for 18 hours. After the reaction is completed, filter and distill under reduced pressure. Purify the crude product by flash silica gel column chromatography [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] + 。

[0381] Step 3: Synthesis of 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0382]

[0383] 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) was added [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium(II) dichloride (512 mg, 0.7 mmol) and sodium tert-butoxide (1.45 g, 15.0 mmol). The mixture was stirred at 100 °C for 5 h under nitrogen protection. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated by flash silica gel column chromatography [eluent: petroleum ether / ethyl acetate: 0 - 30%] to give 3,3-difluoro-1'-(4-methoxybenzyl)-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (2.0 g, yield: 77%). ESI-MS: 345.0 [M+1] + 。

[0384] Step 4: Synthesis of 3,3-difluoro-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0385]

[0386] 3,3-Difluoro-1'-(4-methoxybenzyl)-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-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 completion of the reaction, the crude product was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 50%] to give 3,3-difluoro-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (1.1 g, yield: 93%). ESI-MS: 225.0 [M+1] + 。

[0387] Step 5: Synthesis of 3,3-difluoro-5'-methyl-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]

[0388]

[0389] Dissolve 3,3-difluoro-5'-methylspiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (250 mg, 1.1 mmol) in tetrahydrofuran (20 mL), cool to 0 °C, and add dropwise a solution of lithium aluminum hydride in tetrahydrofuran (1.3 mL, 2.5 M) 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 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] + 。

[0390] Intermediate A20: Preparation of tert-butyl 5'-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0391]

[0392] First step: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[0393]

[0394] Dissolve 2-bromo-6-methylpyridin-3-amine (3.5 g, 18.7 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.52 g, 22.5 mmol), and N-methylimidazole (6.45 g, 78.6 mmol) in acetonitrile (55 mL). Add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (7.35 g, 26.42 mmol). The reaction was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (100 mL), and the organic phase was washed successively with water (50 mL) and saturated brine (50 mL). The organic phase was concentrated, and the residue was separated by flash silica gel column [petroleum ether: ethyl acetate = 1:1] to obtain the crude product 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] + 。

[0395] Second step: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

[0396]

[0397] tert-Butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)azetidine-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 under nitrogen protection for 4 hours. After the reaction was completed, the reaction solution was separated with ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was purified by flash silica gel column [petroleum ether / ethyl acetate = 2 / 1] to obtain 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] + 。

[0398] 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

[0399]

[0400] 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(II) dichloride (PEPPSI-iPr) (240 mg, 0.36 mmol), and sodium tert-butoxide (1.03 g, 10.7 mmol) were dissolved in 1,4-dioxane (60 mL). The reaction solution was stirred at 110 °C under microwave irradiation for 18 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The obtained residue was separated with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was concentrated, and the residue was purified by flash silica gel column separation [petroleum ether / ethyl acetate = 3 / 1] to obtain 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] + 。

[0401] Step 4: Synthesis of tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0402]

[0403] 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, and the reaction was completed. The reaction solution was layered with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was separated by rapid silica gel column [petroleum ether / ethyl acetate = 1 / 1] to obtain 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] + .

[0404] Step 5: Synthesis of tert-butyl 5'-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0405]

[0406] 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. The reaction solution was stirred at room temperature for 3 hours under nitrogen protection, and the reaction was completed. The reaction solution was layered with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was separated by rapid silica gel column [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] + .

[0407] Intermediate A21: Preparation of tert-butyl 5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0408]

[0409] Step 1: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate

[0410]

[0411] Dissolve 2-bromo-6-methylpyridin-3-amine (3.0 g, 16.0 mmol), 1-(tert-butyloxycarbonyl)-pyrrolidine-3-carboxylic acid (3.45 g, 16.0 mmol), and N-methylimidazole (5.370 mL, 67.4 mmol) in acetonitrile (100 mL). Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) (6.3 g, 22.4 mmol). The reaction 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 brine (50 mL) in turn. The organic phase was concentrated, and the residue was separated by a rapid silica gel column [petroleum ether: ethyl acetate = 1:1] to obtain 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] + .

[0412] Step 2: Synthesis of tert-butyl 3-((2-bromo-6-methylpyridin-3-yl)(4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate

[0413]

[0414] Tert-butyl 3-((2-bromo-6-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 protection. After the reaction was completed, the reaction solution was separated into layers with ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL). The obtained organic phase was concentrated, and the residue was passed through a fast 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] + .

[0415] 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

[0416]

[0417] 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(II) dichloride (PEPPSI-iPr) (136.20 mg, 0.2 mmol), and sodium tert-butoxide (343 mg, 3.57 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C under microwave irradiation for 5 h. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL). The organic layer was concentrated, and the residue was purified by flash silica gel column chromatography [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] + 。

[0418] Step 4: Synthesis of tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0419]

[0420] 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), and trifluoromethanesulfonic acid (0.74 mL, 8.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL), and the organic layer was washed with saturated brine (50 mL). The organic layer was concentrated, and the residue was purified by flash silica gel column chromatography [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] + 。

[0421] Step 5: Synthesis of tert-butyl 5'-methyl-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate

[0422]

[0423] Dissolve tert-butyl 5'-methyl-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (220 mg, 0.73 mmol) in tetrahydrofuran (10 mL). Add borane tetrahydrofuran solution (7.2 mL, 7.2 mmol) to the reaction solution. Stir the reaction solution at 70 °C for 16 hours under nitrogen protection to end the reaction. Separate the layers of the reaction solution with ethyl acetate (50 mL) and saturated brine (50 mL). Wash the organic phase with saturated brine (50 mL). Concentrate the obtained organic phase, and separate the residue by flash silica gel column chromatography [petroleum ether / ethyl acetate = 1 / 1] to obtain 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] + 。

[0424] Intermediate A22: Preparation of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine

[0425]

[0426] First step: Synthesis of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one

[0427]

[0428] At 0 °C, slowly add nitric acid (65% by mass, 5.4 g, 55.6 mmol) dropwise to concentrated sulfuric acid (98% by mass, 30 mL) of 1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (450 mg, 2.5 mmol). Stir the mixture at 0 °C for 1 hour, slowly pour it into ice water, stir for 1 hour, filter, and dry the filter cake 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] + 。

[0429] Second step: Synthesis of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

[0430]

[0431] 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) was added phosphorus oxychloride (6.4 g, 41.6 mmol) and triethylbenzylammonium chloride (1.9 g, 7.0 mmol). The mixture was stirred at 80 °C for 1 h, concentrated under reduced pressure to remove the solvent, and the residue was slowly poured into ice water and stirred for 30 min. It was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, the crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 50%] to obtain 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (985 mg, yield: 36.0%). ESI-MS: 198.9 [M+1] + 。

[0432] Step 3: Synthesis of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)malonate

[0433]

[0434] At 0 °C, 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). The mixture was stirred at 0 °C for 0.5 h, and diethyl malonate (840 mg, 4.2 mmol) was added to the mixture. The reaction mixture was stirred at 100 °C for 1 h, cooled to room temperature, quenched with saturated ammonium chloride solution, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, the crude product was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 30%] to obtain diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)malonate (409 mg, yield: 30.0%). ESI-MS: 323.0 [M+1] + 。

[0435] Step 4: Synthesis of ethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)acetate

[0436]

[0437] To a solution of diethyl 2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)malonate (409 mg, 1.3 mmol) in dimethyl sulfoxide (5 mL) was added water (0.91 ml, 5.1 mmol) and lithium chloride (267 mg, 6.4 mmol). The mixture was stirred at 100 °C for 24 h. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation 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-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)acetate (240 mg, yield: 76.0%). ESI-MS: 251.0 [M+1] + 。

[0438] Step 5: Synthesis of ethyl 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)propionate

[0439]

[0440] 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) at 0 °C was added methyl iodide (300 mg, 2.1 mmol), 18-crown-6 (26 mg, 0.1 mmol), and then sodium hydride (88 mg, 2.2 mmol) was slowly added. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched with ice water, washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distillation under reduced pressure, the crude product was separated by flash silica gel column chromatography [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] + 。

[0441] Step 6: Synthesis of 3,3-dimethyl-3,5,6,7-tetrahydrocyclopenta[b]pyrrolo[2,3-e]pyridin-2(1H)-one

[0442]

[0443] To a solution of 2-methyl-2-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl) propionate (150 mg, 0.54 mmol) in ethanol (5 mL) was added ammonium formate (272 mg, 4.3 mmol) and 10% palladium on carbon (50 mg). The mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product 3,3-dimethyl-3,5,6,7-tetrahydrocyclopenta[b]pyrrolo[2,3-e]pyridin-2(1H)-one, which was directly used in the next step of the reaction. ESI-MS: 203.0 [M+1] + 。

[0444] Step 7: Synthesis of 3,3-dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine

[0445]

[0446] 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), cooled to 0 °C, and a solution of lithium aluminum hydride in tetrahydrofuran (2 mL, 2.5 M) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. 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-dimethyl-1,2,3,5,6,7-hexahydrocyclopenta[b]pyrrolo[2,3-e]pyridine. ESI-MS: 189.0 [M+1] + 。

[0447] Intermediate B1: Preparation of 1-(2-chloropyridin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0448]

[0449] 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 of N,N-dimethylformamide. A solution of potassium tert-butoxide in tetrahydrofuran (5.6 mL, 1 M, 5.57 mmol) was added to the solution at room temperature. The reaction was stirred at 100 °C for 1 hour. Water was added to the solution, and the mixture was extracted three times with ethyl acetate. After combining the organic phases, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue 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] + 。

[0450] Intermediate B2 - B3 was prepared by referring to the synthesis method of Intermediate B1:

[0451]

[0452] Intermediate B4: Preparation of 1-(2-chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0453]

[0454] 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 successively added into a microwave tube. The reaction solution was reacted at 100 °C by microwave for 18 hours. After the reaction was completed, the solvent was removed to obtain the crude product, and the residue 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] + 。

[0455] Intermediate B5 - B19 was prepared by referring to the synthesis method of Intermediate B4:

[0456]

[0457]

[0458]

[0459] Preparation of Intermediate B20: 1-(4-Chloro-1,3,5-triazin-2-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0460]

[0461] 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. 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 with stirring. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed, and the residue was separated by silica gel column chromatography [petroleum ether: ethyl acetate = 4:1] to obtain 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] + 。

[0462] The preparation of Intermediate B21 was carried out according to the synthetic method of Intermediate B20:

[0463]

[0464] Preparation of Intermediate B22: 1-(6-Chloropyrimidin-4-yl)-3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0465]

[0466] 4,6-Dichloropyrimidine (347 mg, 1.84 mmol) was dissolved in 15 mL of isopropanol. At room temperature, 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. The reaction mixture was heated to 80 °C and stirred for 16 hours. After completion of the reaction, the solvent was removed, and the residue 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] + 。

[0467] The preparations of Intermediates B23 - B25 were carried out according to the synthetic method of Intermediate B22:

[0468]

[0469] Preparation of Intermediate B26: 1-(2-Chloropyrimidin-4-yl)-3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0470]

[0471] Dissolve 3,3-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.44 mmol) in 8 mL of N,N-dimethylformamide. Cool the solution to 0 °C, add sodium hydride (70 mg, 1.75 mmol) to the solution, stir for 0.5 hour, then add 2,4-dichloropyrimidine (261 mg, 1.75 mmol) to the mixture. Stir the reaction mixture at 0 °C for 1 hour, cool to room temperature, quench the reaction with a small amount of water, wash with water, extract with ethyl acetate, dry, remove the solvent, and subject the residue to column chromatography to obtain the product 1-(2-chloropyrimidin-4-yl)-3,3-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] + 。

[0472] The preparations of Intermediates B27 - B28 were obtained by referring to the synthetic method of Intermediate B26:

[0473]

[0474] Preparation of Intermediate B29: 5-Bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0475] First Step: Synthesis of 5-Bromo-3,3-dimethyl-1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0476]

[0477] 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. The solution was cooled to 0 °C, and sodium hydride (563.6 mg, 14 mmol) was added to the solution. The mixture was stirred for 0.5 h, and then 4-chloro-2-(methylthio)pyrimidine (1.13 g, 7.0 mmol) was added. The reaction mixture was stirred at 0 °C for 18 h, cooled to room temperature, quenched with a small amount of water, washed with water, extracted with ethyl acetate, dried, and the solvent was removed. The residue was purified by column chromatography to give 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] + 。

[0478] Step 2: Synthesis of 5-bromo-3,3-dimethyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0479]

[0480] 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 mixed solvent of tetrahydrofuran (10 mL), methanol (10 mL), and water (3 mL), and potassium persulfate (3.29 g, 5.36 mmol) was added. The reaction mixture was stirred at room temperature overnight, filtered, the filtrate was washed with water, extracted with ethyl acetate, dried, and the organic solvents were removed under reduced pressure. The residue was purified by column chromatography to give 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] + 。

[0481] Intermediate C1: N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine Preparation

[0482]

[0483] 4-Fluoro-2-methoxy-5-nitroaniline (1.86 g, 10.0 mmol) was dissolved in 10 mL of N,N-dimethylformamide. At room temperature, N 1 ,N 1 ,N2 -Trimethylethane-1,2-diamine (1.53 g, 15.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol). The reaction was stirred at 85 °C for 3 hours. Water was added to the solution, and the mixture was extracted three times with dichloromethane. After combining the organic phases, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography separation [dichloromethane: methanol = 10:1] gave N 1 -(2-(Dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-2-nitrobenzene-1,4-diamine (2.5 g, yield: 93%). ESI-MS: 269.0 [M+1] + .

[0484] Intermediate C2 was prepared according to the synthetic method of Intermediate C1:

[0485]

[0486] Intermediate C3: 5-(Difluoromethoxy)-N 1 -(2-(Dimethylamino)ethyl)-N 1 -Methyl-2-nitrobenzene-1,4-diamine Preparation

[0487]

[0488] First step: Synthesis of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene

[0489]

[0490] 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-difluoroacetate sodium (33.97 g, 222.79 mmol) was added in batches at 90 °C. The reaction solution was stirred at this temperature for 3 hours and monitored by TLC. After the reaction solution was cooled to room temperature, it was poured into ice water and extracted three times with ethyl acetate. After combining the organic phases, the mixture was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and after concentration under reduced pressure, column chromatography separation [eluent: ethyl acetate / petroleum ether: 0-10%] gave 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, 49.57 mmol, yield: 77.88%).

[0491] 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).

[0492] Step 2: Synthesis of 2-(difluoromethoxy)-4-fluoroaniline

[0493]

[0494] Dissolve 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (10.3 g, 49.73 mmol) in ethanol (80 mL), add palladium on carbon (1.0 g, 10% w / w) thereto, and stir the reaction solution overnight at room temperature under hydrogen. Filter the reaction solution through diatomaceous earth, and concentrate the filtrate to obtain 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 42.99 mmol, yield: 86.42%). ESI-MS: 178.1 [M+1] + 。

[0495] Step 3: Synthesis of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline

[0496]

[0497] Dissolve 2-(difluoromethoxy)-4-fluoroaniline (8.1 g, 45.73 mmol) in concentrated sulfuric acid (40 mL), and add potassium nitrate (5.09 g, 50.30 mmol) thereto at 0 °C. Slowly return the reaction solution to room temperature and stir for 3 hours, monitored by TLC. Pour the reaction solution into ice water, and extract it three times with ethyl acetate. Combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography [from 100% petroleum ether to 15% ethyl acetate] to obtain 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (8.0 g, 35.15 mmol, yield: 76.87%).

[0498] 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).

[0499] Step 4: Synthesis of 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 -methyl-2-nitrobenzene-1,4-diamine

[0500]

[0501] 2-(Difluoromethoxy)-4-fluoro-5-nitroaniline (1 g, 4.50 mmol) was dissolved in acetonitrile (30 mL), and then potassium carbonate (1.24 g, 9.00 mmol) and N 1 ,N 1 ,N 2 ,N-trimethylethane-1,2-diamine (0.863 mL, 6.753 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 3 hours, monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography [eluent: dichloromethane / methanol: 0 - 10%] to obtain 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1 -methyl-2-nitrobenzene-1,4-diamine (1.25 g, 3.74 mmol, yield: 83.03%). ESI-MS: 305.2 [M+1] + .

[0502] The preparation of intermediate C4-C5 was obtained by referring to the synthesis method of intermediate C3: In the first step, sodium 2-chloro-2,2-difluoroacetate was replaced with iodoethane or isopropyl iodide, and the reaction conditions were changed to stir at 37 °C for 18 hours, and the remaining steps were the same.

[0503]

[0504] Preparation of intermediate C6: N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)formamide

[0505]

[0506] N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine (2.68 g, 10 mmol) and formic acid (20 mL) were added to the reaction flask, and the reaction mixture was stirred at 100 °C for 2 hours. 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] + .

[0507] The preparation of intermediate C7 was obtained by referring to the synthesis method of intermediate C6:

[0508]

[0509] Intermediate C8: N 1-(2-(Dimethylamino)ethyl)-N 1 Preparation of -Methyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene-1,4-diamine

[0510]

[0511] Step 1: Synthesis of 4-Fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene

[0512]

[0513] Dissolve 2,4-difluoro-1-nitrobenzene (12.00 g, 75.43 mmol) and cesium carbonate (24.58 g, 75.43 mmol) in tetrahydrofuran (100 mL). Add 2,2,2-trifluoroethanol (5.43 mL, 75.43 mmol) at 0 °C. Stir the reaction mixture at room temperature overnight and monitor by TLC. Pour the reaction mixture into water and extract three times with ethyl acetate. Combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 10%] to obtain 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene (15.8 g, 64.93 mmol, yield: 86.08%).

[0514] 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).

[0515] Step 2: Synthesis of 4-Fluoro-2-(2,2,2-trifluoroethoxy)aniline

[0516]

[0517] Dissolve 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene (15.8 g, 66.08 mmol) in ethanol (80 mL) and water (20 mL). Add iron powder (22.14 g, 396.45 mmol) thereto. Stir the reaction mixture at 80 °C for 5 hours and detect by TLC. Cool the reaction mixture to room temperature, filter through diatomaceous earth, concentrate the filtrate, add water and ethyl acetate, and extract three times. Combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography [eluent: ethyl acetate / petroleum ether: 0 - 10%] to obtain 4-fluoro-2-(2,2,2-trifluoroethoxy)aniline (11.3 g, 52.01 mmol, yield: 78.71%). ESI-MS: 210.1 [M+1]+ 。

[0518] Step 3: Synthesis of 4-Fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)aniline

[0519]

[0520] Dissolve 4-Fluoro-2-(2,2,2-trifluoroethoxy)aniline (11.3 g, 54.03 mmol) in concentrated sulfuric acid (40 mL), and then add potassium nitrate (6.01 g, 59.43 mmol) at 0 °C. The reaction mixture is slowly returned to room temperature and stirred for 3 hours, monitored by TLC. The reaction mixture is poured into ice water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, 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%).

[0521] 1 1H 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).

[0522] Step 4: N 1 -(2-(Dimethylamino)ethyl)-N 1 -Methyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene-1,4-diamine Synthesis

[0523]

[0524] Dissolve 4-Fluoro-5-nitro-2-(2,2,2-trifluoroethoxy)aniline (1.0 g, 3.93 mmol) in acetonitrile (30 mL), and then add potassium carbonate (1.09 g, 7.87 mmol) and N 1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine (0.754 mL, 5.90 mmol). The reaction mixture is heated to 80 °C and stirred for 3 hours, monitored by TLC. After the reaction mixture is cooled to room temperature, it is filtered, and the filtrate is concentrated under reduced pressure and separated by column chromatography [eluent: dichloromethane / methanol: 0 - 10%] to obtain 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%). ESI-MS: 337.1 [M+1] + 。

[0525] Intermediate C9: N 2 -(2-(Dimethylamino)ethyl)-6-methoxy-N 2 -Methyl-3-nitropyridine-2,5-diamine Preparation

[0526]

[0527] First step: Synthesis of 6-bromo-2-methoxy-3-nitropyridine

[0528]

[0529] Under ice bath, 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). The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and ethyl acetate was added for extraction. The organic phases were combined, washed with saturated brine, and after concentration, 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] + 。

[0530] Second step: Synthesis of 6-bromo-2-methoxypyridin-3-amine

[0531]

[0532] In 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 was stirred at about 90 °C for 3 hours. It was separated into layers with dichloromethane and water. After concentration of the organic phase, separation by column chromatography [petroleum ether: ethyl acetate = 3:1] gave 6-bromo-2-methoxypyridin-3-amine (9.1 g, yield: 75%). ESI-MS: 203.1 [M+1] + 。

[0533] 1H 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).

[0534] Step 3: Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)acetamide

[0535]

[0536] Under ice bath, 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). The reaction was stirred at ice bath for 1 h. The mixture was separated with dichloromethane and water, and the organic phase was concentrated and 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%). It was directly used for the next step.

[0537] Step 4: Synthesis of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide

[0538]

[0539] Under ice bath, concentrated nitric acid (65%, 46.6 mmol) was added to a solution of N-(6-bromo-2-methoxypyridin-3-yl)acetamide (9.5 g, 38.9 mmol) in trifluoroacetic anhydride (80 mL). The reaction was stirred at ice bath for 1 h. The reaction solution was slowly poured into ice water, stirred for 1 h, and a solid was precipitated. It was filtered by suction, and 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] + 。

[0540] 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.12 (s, 1H), 4.06 (s, 3H), 2.16 (s, 3H).

[0541] Step 5: Synthesis of N-(6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitropyridin-3-yl)acetamide

[0542]

[0543] To a solution of N-(6-bromo-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 3.4 mmol) in acetonitrile (20 mL), N 1 ,N 1 ,N 2-Trimethylethane-1,2-diamine (520 mg, 5.1 mmol). The reaction solution was stirred at 80 °C for 1 hour. After removing the solvent, silica gel column chromatography [dichloromethane:methanol = 10:1] was used 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] + 。

[0544] Step 6: Synthesis of N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 -methyl-3-nitropyridine-2,5-diamine

[0545]

[0546] 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 was stirred at 60 °C for 5 hours. The mixture was separated with saturated sodium bicarbonate solution and dichloromethane. After concentration of the organic phase, N 2 -(2-(dimethylamino)ethyl)-6-methoxy-N 2 -methyl-3-nitropyridine-2,5-diamine (645 mg, yield: 100%). ESI-MS: 270.3 [M+1] + 。

[0547] Intermediates C10 - C11 were prepared according to the preparation method of Intermediate C9: 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 preparation

[0548]

[0549] 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. At room temperature, N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N1 -Methyl-2-nitrobenzene-1,4-diamine (254 mg, 0.95 mmol), cesium carbonate (926 mg, 2.85 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (177 mg, 0.285 mmol), and palladium acetate (31 mg, 0.145 mmol). After evacuating and replacing nitrogen three times, the reaction was stirred at 110 °C for 2 hours. Water was added to the solution, and the mixture was extracted three times with dichloromethane. After combining the organic phases, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography separation [dichloromethane:methanol = 10:1] gave 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%). ESI-MS: 492.2 [M+1] + .

[0550] Intermediates D2-D46, D47-2, and D48-2 were prepared by referring to the synthesis method of Intermediate D1:

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] Intermediate D49-1: Preparation 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

[0560]

[0561] 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), palladium acetate (20.24 mg, 0.09 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (112.24 mg, 0.17 mmol) and 1,4-dioxane (15 mL) were successively added to a reaction flask. The reaction solution was purged with nitrogen three times and stirred at 120 °C for 2 h under nitrogen protection. After filtration, 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-pyrrolo[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] + 。

[0562] Intermediates D50-1 and D51-1 were prepared by referring to the synthesis method of Intermediate D49-1:

[0563]

[0564] 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

[0565]

[0566] To a solution 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 (100 mg, 0.23 mmol) in 1,4-dioxane (20 mL) was added (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). The reaction was stirred at 120 °C for 18 h. Dichloromethane and water were used for liquid separation. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [dichloromethane:methanol = 10:1] to obtain (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] + 。

[0567] Intermediates D50 - D52 were prepared by referring to the synthetic method of Intermediate D49:

[0568]

[0569]

[0570] Intermediate D53-1: Preparation 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

[0571]

[0572] First step: Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine

[0573]

[0574] 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 successively. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain the crude product, dichloromethane (80 mL) was added, and after stirring for 30 minutes, it was 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-triazin-2-amine (10.15 g, yield: 63%), ESI-MS: 300.1 [M+1] + 。

[0575] 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

[0576]

[0577] To a solution of 3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.63 mmol) in 1,4-dioxane (20 mL) were 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 was stirred at 120 °C for 2 hours. Dichloromethane and water were used for liquid separation. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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, which was directly used in the next step. ESI-MS: 426.2 [M+1] + 。

[0578] Intermediates D54-1 to 64-1 were prepared by referring to the synthesis method of Intermediate D53-1:

[0579]

[0580]

[0581] Intermediate D53: N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1-Methyl-2-nitro-N 4 Preparation of N-(4-(3,3,5-Trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)-1,4-benzenediamine

[0582]

[0583] To a solution of the crude 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) were added dimethyl[2-(methylamino)ethyl]amine (95 mg, 0.95 mmol) and diisopropylethylamine (82 mg, 0.95 mmol). The reaction was stirred at 120 °C for 18 hours. The mixture was separated with dichloromethane and water. The organic layer was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography [dichloromethane:methanol = 10:1] to obtain N 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)-1,4-benzenediamine (130 mg). ESI-MS: 508.2 [M+1] + .

[0584] Intermediates D54-D63 and D64-2 were prepared according to the synthetic method of Intermediate D53:

[0585]

[0586]

[0587]

[0588] 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-nitro-1,4-benzenediamine preparation

[0589]

[0590] tert-Butyl 1'-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)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 dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated to dryness after completion of the reaction, and the residue was dissolved in methanol (3 mL) and water (20 mL). An aqueous formaldehyde solution (5 mL) and diisopropylethylamine (51 mg, 0.39 mmol) were added to the reaction solution. After stirring for 10 minutes, sodium cyanoborohydride (50 mg, 0.80 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was extracted with dichloromethane (50 mL) and water (50 mL) by partitioning. The organic phase was dried and concentrated to obtain 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 (40 mg, 0.073 mmol, yield: 92.57%). ESI-MS: 518.2 [M+1] + 。

[0591] Intermediates D48 and D64 were prepared by referring to the synthesis method of Intermediate D47:

[0592]

[0593] Intermediate D65: Preparation of 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

[0594]

[0595] To 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 5-(difluoromethoxy)-N 1 -(2-(dimethylamino)ethyl)-N 1-Methyl-2-nitrobenzene-1,4-diamine (166 mg, 0.54 mmol) and p-toluenesulfonic acid monohydrate (125 mg, 0.54 mmol). The reaction was stirred at 120 °C for 2 h. It was separated with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography [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%). ESI-MS: 544.1 [M+1] + .

[0596] The preparation of intermediate D66 was obtained by referring to the synthesis method of intermediate D65:

[0597]

[0598]

[0599] Intermediate D67: N 1 -(2-(Dimethylamino)ethyl)-5-ethoxy-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 Preparation

[0600]

[0601] To 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 N 1 -(2-(Dimethylamino)ethyl)-5-ethoxy-N 1 -Methyl-2-nitrobenzene-1,4-diamine (153.6 mg, 0.54 mmol) and trifluoroacetic acid (124 mg, 1.09 mmol). The reaction was stirred at 120 °C for 2 h. It was separated with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography [dichloromethane:methanol = 10:1] to obtain N 1-(2-(Dimethylamino)ethyl)-5-ethoxy-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%). ESI-MS: 522.3 [M+1] + 。

[0602] The preparation of intermediates D68 - D70 was carried out with reference to the synthesis method of intermediate D67:

[0603]

[0604]

[0605] 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 preparation

[0606]

[0607] 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 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 stirred for 1 hour. After the reaction was completed, it was separated with ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography [petroleum ether: ethyl acetate = 4:1] to obtain 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 (543 mg, yield: 91.2%). ESI-MS: 571.2, 573.2 [M+1]+ .

[0608] The preparation of intermediate D72 was obtained by referring to the synthesis method of intermediate D71:

[0609]

[0610] 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 -methylbenzene-1,2,4-triamine preparation

[0611]

[0612] Dissolve 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, 0.68 mmol) in a mixed solvent of ethanol / water at 20 mL / 10 mL. At room temperature, iron powder (228 mg, 4.08 mmol) and ammonium chloride (228 mg, 4.08 mmol) were added to the solution. The reaction was stirred at 90 °C for 3 hours. Water was added to the solution, and it was extracted three times with dichloromethane. After combining the organic phases, it was washed with saturated brine 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%). ESI-MS: 462.4 [M+1] + .

[0613] The preparation of intermediates E2 - E29 was obtained by referring to the synthesis method of intermediate E1:

[0614]

[0615]

[0616]

[0617]

[0618] 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 Preparation

[0619]

[0620] Dissolve N 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) in 5 mL of methanol. Add 10% palladium on carbon (20 mg) to the solution. Replace the reaction solution with hydrogen three times and stir at room temperature in a hydrogen atmosphere for 3 hours. After the reaction is completed, filter 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%). ESI-MS: 477.3 [M+1] + .

[0621] The preparations of Intermediates E31 - E68 are obtained by referring to the synthetic method of Intermediate E30:

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628] Intermediate E69: 5-(Difluoromethoxy)-N 1 -(2-(Dimethylamino)ethyl)-N 1 -methyl-N 4Preparation of -(4-(3,3,5-Trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine

[0629]

[0630] In a methanol (6 mL) solution of 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, 0.37 mmol), zinc powder (482 mg, 7.36 mmol) and ammonium chloride (394 mg, 7.36 mmol) were added. The reaction was stirred at room temperature for 3 hours. The reaction solution was filtered through diatomaceous earth, concentrated and separated by silica gel column chromatography [methylene chloride: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%). ESI-MS: 514.1 [M+1] + .

[0631] The intermediate E70 was prepared by referring to the synthesis method of intermediate E69:

[0632]

[0633] Intermediate F1: Preparation of 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

[0634]

[0635] To 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 1-Methylbenzene-1,2,4-triamine (194 mg, 0.36 mmol) was dissolved in anhydrous acetonitrile / water (3 mL / 1 mL). N,N-Diisopropylethylamine (138 mg, 1.08 mmol) was added to the solution. The reaction mixture was added with acryloyl chloride (97.3 mg, 1.08 mmol) at 0 °C. After the reaction was completed, it was separated with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography [40 - 50% acetonitrile / water] to 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)(methyl)amino)-4-methoxyphenyl)acrylamide (150 mg, yield: 56.2%). ESI-MS: 595.2, 597.2 [M+1] + .

[0636] Intermediate F2 was prepared by referring to the synthesis method of Intermediate F1:

[0637]

[0638] 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

[0639]

[0640] 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), trimethylsilylacetylene (247 mg, 2.5 mmol), triethylamine (509 mg, 5.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (58 mg, 0.076 mmol) and copper(I) iodide (14.4 mg, 0.076 mmol) were dissolved in tetrahydrofuran (6 mL). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection until the reaction was completed. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was separated by flash silica gel column chromatography [dichloromethane:methanol = 10:1] to obtain 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] + 。

[0641] Intermediate G2 was prepared according to the synthetic method of Intermediate G1 as follows:

[0642]

[0643] II. Preparation of Compounds in Specific Examples

[0644] 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

[0645]

[0646] 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, 0.44 mmol) was dissolved in anhydrous dichloromethane (5 mL). N,N-Diisopropylethylamine (170 mg, 1.32 mmol) was added to the solution. The reaction mixture was added acryloyl chloride (67 mg, 0.75 mmol) at 0 °C. After concentration, separation by reverse-phase column chromatography [40 - 50% acetonitrile / water] gave 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] + 。

[0647] 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).

[0648] 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

[0649]

[0650] 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). N,N-Diisopropylethylamine (66 mg, 0.51 mmol) was added to the solution. The reaction mixture was added acryloyl chloride (23 mg, 0.25 mmol) at 0 °C. After stirring for half an hour, the reaction mixture was quenched with 0.5 mL of methanol, and 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%) was obtained by preparative high performance liquid chromatography. ESI-MS: 568.2 [M+1] + 。

[0651] 1 H 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 = 17.7 Hz, 5H), 2.21 (s, 6H), 1.29 (s, 6H).

[0652] The preparations of the following examples were obtained by referring to the synthesis methods of Example 1 or Example 9:

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664] The NMR data of the compounds prepared in the above examples are as follows:

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674] 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

[0675]

[0676] 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), potassium carbonate (19.3 mg, 0.14 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After filtration, the solvent was removed from the filtrate, and the residue was separated by reverse-phase column chromatography [40 - 50% acetonitrile / water] to obtain 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] + 。

[0677] 1 1H NMR (400 MHz, 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).

[0678] The preparation of Example 68 was carried out according to the synthetic method of Example 54 to obtain:

[0679]

[0680]

[0681] The NMR data of the compounds prepared in the above examples are as follows:

[0682]

[0683] 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

[0684]

[0685] First step: 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

[0686]

[0687] 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-dioxaborolan-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), toluene (3 mL). The mixture was purged with nitrogen three times and heated to 110 °C with stirring for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by flash silica gel column chromatography [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] + .

[0688] 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

[0689]

[0690] Dissolve 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, 0.055 mmol) in 5 mL of methanol. Add 10% palladium on carbon (10 mg) to the solution. Replace the reaction solution with hydrogen three times and stir at room temperature in a hydrogen atmosphere for 1 hour. After the reaction is completed, filter 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%) is obtained. ESI-MS: 629.4 [M+1] + 。

[0691] Step 3: Synthesis of tert-butyl 4-(1-(2-((5-acrylamido-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

[0692]

[0693] Dissolve tert-butyl 4-(1-(2-((5-acrylamido-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) in anhydrous acetonitrile / water (1 mL / 0.3 mL). Add N,N-diisopropylethylamine (18 mg, 0.143 mmol) to the solution. Add acryloyl chloride (13.0 mg, 0.143 mmol) to the reaction solution at 0 °C. After the reaction is completed, separate the layers with dichloromethane and water. Wash the organic phase successively with water and saturated sodium chloride, then dry over anhydrous sodium sulfate, filter, concentrate, and separate by reverse-phase column chromatography [40 - 50% acetonitrile / water] to obtain tert-butyl 4-(1-(2-((5-acrylamido-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 (300 mg, yield: 64.5%). ESI-MS: 683.4 [M+1] + 。

[0694] 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

[0695]

[0696] Dissolve tert-butyl 4-(1-(2-((5-acrylamido-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, 0.044 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), stir the reaction solution at room temperature for 2 hours, remove the solvent, and 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)(methyl)amino)-4-methoxyphenyl)acrylamide (5 mg, yield: 18.5%) by reverse-phase column chromatography of the residue. ESI-MS: 583.3 [M+1] + 。

[0697] 1 HNMR (400 MHz, 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).

[0698] 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

[0699]

[0700] The first step: 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 -methyl-5-nitrobenzene-1,4-diamine synthesis

[0701]

[0702] 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), copper(I) iodide (6.3 mg, 0.033 mmol), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (9.5 mg, 0.066 mmol), dimethyl sulfoxide (2 mL). The mixture was purged with nitrogen three times, and then heated to 110 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by flash silica gel column chromatography [eluent: methanol / dichloromethane: 0 - 10%] to obtain 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%). ESI-MS: 287.0 [M+1] + .

[0703] 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] + .

[0704] Step 2: Synthesis of 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

[0705]

[0706] Take 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 (17 mg, 0.055 mmol) was dissolved in 5 mL of methanol. 10% palladium on carbon (10 mg) was added to the solution. The reaction mixture was purged with hydrogen three times and stirred at room temperature in a hydrogen atmosphere for 1 hour. After completion of the reaction, it 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%). ESI-MS: 543.2 [M+1] + .

[0707] 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

[0708]

[0709] Take 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, 0.018 mmol) was dissolved in anhydrous acetonitrile / water (1 mL / 0.3 mL). N,N-Diisopropylethylamine (7 mg, 0.055 mmol) was added to the solution. The reaction mixture was added with acryloyl chloride (5 mg, 0.055 mmol) at 0 °C. After the reaction was completed, the mixture was separated with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography [40 - 50% acetonitrile / water] to 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] + 。

[0710] 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, 2.0 Hz, 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).

[0711] 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

[0712]

[0713] The first step: 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 Synthesis

[0714]

[0715] Dissolve 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, 0.093 mmol) in 5 mL of methanol. Add 10% palladium on carbon (10 mg) to the solution. Replace the reaction solution with hydrogen three times and stir at room temperature for 1 hour in a hydrogen atmosphere. After the reaction, filter 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%). ESI-MS: 543.2 [M+1] + 。

[0716] 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

[0717]

[0718] Dissolve 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, 0.059 mmol) was dissolved in anhydrous acetonitrile / water (1 mL / 0.3 mL). N,N-Diisopropylethylamine (22.8 mg, 0.177 mmol) was added to the solution. The reaction mixture was added with acryloyl chloride (16 mg, 0.177 mmol) at 0 °C. After the reaction was completed, dichloromethane and water were used for liquid separation. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography [40 - 50% acetonitrile / water] to 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] + .

[0719] 1 HNMR (400 MHz, 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, 2.1 Hz, 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).

[0720] Biological test evaluation

[0721] I. Cell Proliferation Assay

[0722] (I) Reagents and Consumables

[0723] Fetal bovine serum FBS (GBICO, Cat#10099-141);

[0724] Luminescent cell viability assay kit (Promega, Cat#G7572);

[0725] Black transparent flat-bottom 96-well plates, ( Cat#3603)

[0726] (II) Instruments

[0727] SpectraMax multi-label microplate reader MD, 2104-0010A;

[0728] Carbon dioxide incubator, Thermo Scientific 3100 series;

[0729] Biological safety cabinet, Thermo Scientific, Model 1300 series A2;

[0730] Inverted microscope, Olympus, CKX41SF;

[0731] Siemens refrigerator KK25E76TI.

[0732] (III) Cell lines and culture conditions

[0733]

[0734]

[0735] (IV) Experimental procedures

[0736] 1. Cell culture and seeding:

[0737] (1) Harvest cells in the logarithmic growth phase and count the cells using a hemocytometer. Detect cell viability by trypan blue exclusion method to ensure that the cell viability is above 90%.

[0738] (2) Adjust the cell concentration to reach the final density; add 90 μL of cell suspension to a 96-well plate.

[0739] (3) Incubate the cells in the 96-well plate overnight at 37 °C, 5% CO2 and 95% humidity.

[0740] 2. T0 baseline data:

[0741] (1) Add 10 μL of PBS to each well of the T0 plate containing cells.

[0742] (2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0743] (3) Add an equal volume of CTG solution to each well.

[0744] (4) Vortex on an orbital shaker for 5 minutes to lyse the cells.

[0745] (5) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0746] Read the luminescence signal value of T0.

[0747] 3. Compound dilution and addition

[0748] (1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10 mM stock solution.

[0749] (2) Prepare compound solutions diluted 1000-fold and 3.16-fold.

[0750] (3) Dilute the 1000× diluted compound solution 100-fold with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μM, 9 concentrations, diluted 3.16-fold. Add 10 μL of the drug solution to each well of the 96-well plate seeded with cells. Set three replicate wells for each compound concentration, and the final concentration of DMSO is 0.1%.

[0751] (4) Place the cells in the 96-well plate containing the drug at 37 °C, 5% CO2 and 95% humidity, continue to culture for 72 hours, and then perform CTG analysis.

[0752] 4. Luminescence signal reading

[0753] (1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0754] (2) Add an equal volume of CTG solution to each well.

[0755] (3) Vortex on an orbital shaker for 5 minutes to lyse the cells.

[0756] (4) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0757] (5) Read the luminescence value.

[0758] 5. Data processing

[0759] Analyze the data using GraphPad Prism 7.0 software and fit the data with a non-linear S-curve regression to obtain a dose-response curve, and calculate the IC 50 value (unit: nM). The specific experimental results are shown in Table 1.

[0760] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0761] Table 1: Biological test results

[0762]

[0763]

[0764]

[0765] From the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have a strong inhibitory effect on the EGFR exon 20 insertion mutation at the cellular level and have high selectivity for EGFR WT. Under the same test conditions, the cellular inhibitory activity of the compounds in some examples of the present invention is increased by several times compared with the positive compound.

[0766] All documents mentioned in the present invention are cited herein by reference as if each individual document was specifically and individually cited by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A compound of formula (IIIa1) or a pharmaceutically acceptable salt thereof: Wherein, R2 and R3 are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl and dideuteriomethyl, or R2 and R3 together with the carbon atom to which they are directly attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R4 is hydrogen, deuterium or methyl; R5, R7 and R8 are each independently hydrogen or methyl; R 9a selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl and dideuteriomethyl.

2. The compound of formula (IIIa1) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Selected from the following compounds:

3. A process for preparing the compound of formula (IIIa1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Comprising the following steps: wherein, X1 is fluorine, chlorine, or bromine; R2, R3, R4, R5, R7, R8, and R 9a are as defined in claim 1.

4. A pharmaceutical composition comprising the compound of formula (IIIa1) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 and a pharmaceutically acceptable carrier.

5. Use of the compound of formula (IIIa1) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of a medicament for the treatment and / or prevention of at least partially cancer, tumor or metastatic disease associated with EGFR exon 20 insertion mutation.

6. Use of the compound of formula (IIIa1) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of a medicament for the prevention and / or treatment of at least partially lung cancer, pancreatic cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumors, urological tumor, skin tumor, sarcoma, nasal and paranasal sinus inverted papilloma or nasal and paranasal sinus squamous cell carcinoma associated with nasal and paranasal sinus inverted papilloma.

7. The use according to claim 6, characterized in that, The lung cancer is non-small cell lung cancer; the gastrointestinal tumor is gastric cancer or colon cancer; the head and neck tumor is head and neck cancer; the breast and other gynecological tumors are breast cancer, ovarian cancer or uterine cancer.

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