Pyrimidine-4,6-diamine derivatives, their preparation methods and pharmaceutical applications

Abstract

The present invention relates to pyrimidine-4,6-diamine derivatives, their preparation methods and pharmaceutical applications. In particular, the present invention relates to a pyrimidine-4,6-diamine derivative 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 preparation of a drug for treating and / or preventing at least partially cancer, tumor or metastatic disease associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, especially its use in the preparation of a drug for treating and / or preventing hyperproliferative diseases and diseases of impaired induction of cell death. 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 pyrimidine-4,6-diamine derivatives, a preparation method thereof, and a pharmaceutical application thereof. Background Art

[0002] Lung cancer is the malignant tumor with the highest mortality rate globally, seriously threatening human health. Among them, non-small-cell lung cancer (NSCLC) accounts for approximately 85% of the total number of lung cancers (Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 68, 394 - 424, 2018). Currently, various molecular mechanisms such as multiple gene mutations and abnormal expressions have been confirmed to be related to the onset of NSCLC. Among them, EGFR is the main driver gene. The frequency of EGFR activating mutations in NSCLC patients globally is approximately 17% (Hirsch, F. R. et al. Lung cancer: current therapies and new targeted treatments. Lancet 389, 299 - 311, 2017). The East Asian population is more sensitive, and the mutation frequency is approximately 50% (Passaro, A., P.A., Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377–391, 2021). EGFR activating mutations mainly occur in exons 18-21. Deletion mutations in exon 19 (Del19) and the L858R point mutation in exon 21 are the most common mutation subtypes, accounting for more than 80% of all mutation types (Passaro, A. et al. Recent Advances on the Role of EGFRTyrosine Kinase Inhibitors in the Management of NSCLC With Uncommon, Non Exon20 Insertions, EGFR Mutations. Journal of thoracic oncology: officialpublication of the International Association for the Study of Lung Cancer 16, 764-773, 2021). These mutations can lead to ligand-independent receptor activation and promote the survival and proliferation of tumor cells. The first and second generation EGFR tyrosine kinase inhibitors (Tyrosine Kinase Inhibitor, TKI) are mainly targeted at these two activating mutations. Compared with platinum-based chemotherapy, the first and second generation EGFR TKIs can significantly prolong the progression-free survival (Rosell, R. et al. Erlotinib versus standard chemotherapy as first-linetreatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase3trial. The Lancet. Oncology 13, 239-246, 2012); (Sequist, L.V. et al. Phase IIIstudy of afatinib or cisplatin plus pemetrexed in patients with metastaticlung adenocarcinoma with EGFR mutations.Journal of clinical oncology: official journal of the American Society of Clinical Oncology 31, 3327 - 3334, 2013), but drug resistance often occurs after 10 - 12 months of treatment (Mitsudomi, T. et al. Gefitinib versus cisplatin plus docetaxel in patients with non - small - cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The Lancet. Oncology 11, 121 - 128, 2010); (Park, K. et al. Afatinib versus gefitinib as first - line treatment of patients with EGFR mutation - positive non - small - cell lung cancer (LUX - Lung 7): a phase 2B, open - label, randomised controlled trial. The Lancet. Oncology 17, 577 - 589, 2016). The EGFRT790M mutation is the main mechanism of resistance to first - and second - generation EGFR TKIs. Subsequently, the third - generation EGFR TKI osimertinib was developed to selectively inhibit EGFR T790M and common EGFR mutations. In the results of the phase 3 clinical study FLAURA, osimertinib showed superior efficacy compared with first - generation EGFR TKIs, significantly improving progression - free survival (18.9 vs 10.2 months) and overall survival (38.6 vs 31.8 months) (Soria, J. C. et al. Osimertinib in Untreated EGFR - Mutated Advanced Non - Small - Cell Lung Cancer. The New England journal of medicine 378, 113 - 125, 2018), which also directly promoted osimertinib to the frontline treatment regimen queue.

[0003] Although the efficacy of osimertinib is remarkable, drug resistance inevitably occurs and leads to disease progression. Several EGFR-dependent (on-target) and independent (off-target) drug resistance mechanisms have been reported in preclinical and clinical studies (Passaro, A., P.A., Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377–391, 2021). The analysis of the phase III FLAURA study showed that in the first-line treatment of advanced NSCLC with osimertinib, about 10-15% of patients showed EGFR-dependent drug resistance, and C797S on exon 20 was the most important off-target mutation, accounting for 7% (Ramalingam, S.S. et al. LBA50 Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 2018). The C797S mutation is located in the tyrosine kinase domain of EGFR, preventing osimertinib from forming a covalent bond within the ATP-binding domain of EGFR, thus resulting in drug resistance. In addition, there is no evidence that patients treated with osimertinib first-line will develop acquired mutations in EGFR T790M (Ramalingam, S.S. et al. LBA50 Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 2018). Therefore, the double mutation composed of Del19 / L858R and C797S may be one of the important mechanisms of resistance to first-line osimertinib treatment (Tumbrink, H.L., Heimsoeth, A. & Sos, M.L. The next tier of EGFR resistance mutations in lung cancer. Oncogene 40, 1-11, 2021), and a new generation of EGFR TKI with high activity and selectivity against the double mutation composed of Del19 / L858R and C797S has the potential to be a new treatment option after first-line osimertinib treatment failure, meeting the clinical needs of this group of patients. Summary of the Invention

[0004] The object of the present invention is to provide pyrimidine-4,6-diamine derivatives, their preparation methods and pharmaceutical applications. The series of compounds of the present invention have strong inhibitory effects on the cytological activities of EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, and have high selectivity for EGFR wild type. They 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 Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, especially drugs for treating hyperproliferative diseases and inducing cell death disorder diseases, thus promising to develop a new generation of EGFR inhibitors.

[0005] In the first aspect of the present invention, there is provided a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt:

[0006]

[0007] Wherein, X1 and X2 are each independently N or CR7;

[0008] Z is N or CH;

[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, 3-12 membered heteroaryl, C 6-10 aryl, 5-10 membered heteroaryl, hydroxy, C 1-10 alkoxy, C 3-12 cycloalkoxy, 3-12 membered heteroaryloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, -SF5, -S(O) r R8, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 and -C(O)NR 11 R 12 , and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxy, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C3-12 cycloalkyl, C 3-12 cycloalkoxy, 3 - 12 - membered heterocyclic group, 3 - 12 - membered heterocyclic oxy group, C 6-10 aryl, C 6-10 aryloxy, 5 - 10 - membered heteroaryl, 5 - 10 - membered heteroaryloxy and - NR 11 R 12 is substituted by the substituents of;

[0010] R2 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 - 12 - membered heterocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, - C 0-8 alkyl - SF5, - C 0-8 alkyl - S(O) r R8, - C 0-8 alkyl - O - R9, - C 0-8 alkyl - C(O)OR9, - C 0-8 alkyl - C(O)R 10 , - C 0-8 alkyl - O - C(O)R 10 , - C 0-8 alkyl - NR 11 R 12 , - C 0-8 alkyl - C(=NR 11 )R 10 , - C 0-8 alkyl - N(R 11 ) - C(=NR 12 )R 10 and - C 0-8 alkyl - C(O)NR 11 R 12 , and the above - mentioned groups are independently and optionally further substituted by one or more selected from 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, =O, - C 0-8 alkyl - SF5, - C 0-8 alkyl - S(O) r R8, - C 0-8 alkyl - O - R9, - C 0-8 alkyl - C(O)OR9, - C0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0011] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic group, or, R3 and R4 together with the nitrogen atom to which they are directly connected form a 4-12 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, 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, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 is substituted by substituents of, and the above groups are optionally further substituted by one or more substituents 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;

[0012] Each R5 is 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- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 , or, when m≥2, two adjacent R5 together with the moiety directly connected thereto form a C 5-10 cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, and the above groups are independently 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R10 and -C 0-8 alkyl -C(O)NR 11 R 12 and -C 0-8 alkyl -N(R 11 )-C(O)R 10 substituted by the substituents of;

[0013] R6 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 - 12 membered heterocyclic group, C 6-10 aryl, 5 - 10 membered heteroaryl, -C 0-8 alkyl -SF5, -C 0-8 alkyl -S(O) r R8, -C 0-8 alkyl -O-R9, -C 0-8 alkyl -C(O)OR9, -C 0-8 alkyl -C(O)R 10 and -C 0-8 alkyl -O-C(O)R 10 and -C 0-8 alkyl -NR 11 R 12 and -C 0-8 alkyl -C(=NR 11 )R 10 and -C 0-8 alkyl -N(R 11 )-C(=NR 12 )R 10 and -C 0-8 alkyl -C(O)NR 11 R 12 and -C 0-8 alkyl -N(R 11 )-C(O)R 10 , and the above groups are independently optionally further substituted by one or more selected from 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, =O, -C 0-8 alkyl -SF5, -C 0-8 alkyl -S(O) r R8, -C 0-8alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituted by the substituents of;

[0014] Each R7 is 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- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11)-C(O)R 10 or two R7s together with the moiety to which they are directly attached form a C 5-10 cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, and the above groups are each independently 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;

[0015] Each R8 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 11 R 12 , and the above groups are each independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C3-12 cycloalkyloxy, 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 11 R 12 is substituted by a substituent of;

[0016] Each R9 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 independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, 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 11 R 12 is substituted by a substituent of;

[0017] Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, 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 11 R 12 , and the above groups are independently 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 cycloalkyloxy, 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 11 R 12 is substituted by a substituent of;

[0018] Each R 11 and R12 Each independently selected from hydrogen, deuterium, hydroxyl, 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 independently 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;

[0019] Alternatively, R 11 and R 12 together with the nitrogen atom directly connected thereto form a 4- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocyclic group or 5- to 10-membered heteroaryl is 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;

[0020] m is 0, 1, 2, 3, 4 or 5; and

[0021] each r is independently 0, 1 or 2.

[0022] As a preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, X1 and X2 are each independently N or CR7;

[0023] R1 is 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- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, hydroxy, C 1-4 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heteroalkoxy, C 6-8 aryloxy, 5- to 8-membered heteroaryloxy, -SF5, -S(O) r R8, -C(O)OR9, -C(O)R 10 and -O-C(O)R 10 , and the above groups are independently 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 heteroalkoxy, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 11 R 12 ;

[0024] R2 is 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- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-O-C(O)R 10 , -C 0-4alkyl-NR 11 R 12 、-C 0-4 alkyl-C(=NR 11 )R 10 、-C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-4 alkyl-C(O)NR 11 R 12 ,wherein the above groups are each independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, 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, =O, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 、-C 0-4 alkyl-O-C(O)R 10 、-C 0-4 alkyl-NR 11 R 12 、-C 0-4 alkyl-C(=NR 11 )R 10 、-C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;

[0025] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6a cycloalkyl group and a 3- to 6-membered heterocyclic group, or R3 and R4 together with the nitrogen atom directly connected thereto form a 4- to 12-membered monocyclic heterocyclic group or a polycyclic 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, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, =O, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-O-C(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 , 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- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, =O, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0026] Each R5 is 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, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 , or, when m≥2, two adjacent R5 and their directly connected parts together form a C 5-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-8An aryl or 5- to 8-membered heteroaryl, each of the above groups being independently optionally further substituted by one or more substituents selected from 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, =O, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-O-C(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;

[0027] R6 is 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- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-O-C(O)R 10 , -C0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 The above groups are independently optionally further substituted with one or more selected from 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, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent;

[0028] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3 - 6 - membered heterocyclic group, C 6-8 Aryl, 5 - 8 - membered heteroaryl, -C 0-4 Alkyl - SF5, -C 0-4 Alkyl - S(O) r R8, -C 0-4 Alkyl - O - R9, -C 0-4 Alkyl - C(O)OR9, -C 0-4 Alkyl - C(O)R 10 , -C 0-4 Alkyl - O - C(O)R 10 , -C 0-4 Alkyl - NR 11 R 12 , -C 0-4 Alkyl - C(=NR 11 )R 10 , -C 0-4 Alkyl - N(R 11 ) - C(=NR 12 )R 10 , -C 0-4 Alkyl - C(O)NR 11 R 12 and -C 0-4 Alkyl - N(R 11 ) - C(O)R 10 , or, two R7 together with the moiety directly attached thereto form a C 5-8 Cycloalkyl, 5 - 8 - membered heterocyclic group, C 6-8 Aryl or 5 - 8 - membered heteroaryl, and the above groups are independently 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 - 6 - membered heterocyclic group, C 6-8 Aryl, 5 - 8 - membered heteroaryl, =O, -C 0-4 Alkyl - SF5, -C 0-4 Alkyl - S(O) r R8, -C 0-4 Alkyl - O - R9, -C 0-4 Alkyl - C(O)OR9, -C 0-4 Alkyl - C(O)R 10 , -C 0-4 Alkyl - O - C(O)R 10 , -C 0-4alkyl-NR 11 R 12 、 -C 0-4 alkyl-C(=NR 11 )R 10 、 -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 、 -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 substituted by the substituents of;

[0029] wherein, R8, R9, R 10 , R 11 , R 12 , m and r are as described for the compound of formula (I).

[0030] 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 (II) as follows:

[0031]

[0032] wherein, X1 and X2 are each independently N or CR7;

[0033] Z is N or CH;

[0034] Y is a bond, O, S, N(R 14 ) or C(R 15 R 16 );

[0035] 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, hydroxy, C 1-4 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heteroalkoxy, C 6-8 aryloxy and 5-8 membered heteroaryloxy, and the above groups are independently optionally further substituted by one or more 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 heteroalkoxy, C 6-8Aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 11 R 12 is substituted by substituents;

[0036] R2 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 R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 and -C(O)NR 11 R 12 , and the above groups are independently optionally further substituted by one or more substituents selected from 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, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0037] R 5a , R 5b , R 5c , R5d and R 5e are each independently 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, 5- to 8-membered heteroaryl, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0038] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, 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 R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0039] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4Alkyl, 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 R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0040] R 13a , R 13b , R 13c and R 13d each independently 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, 5- to 8-membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O) r R8, -C 0-4 alkyl-O-R9, -C 0-4 alkyl-C(O)OR9, -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-O-C(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R10 、 -C 0-4 alkyl - C(O)NR 11 R 12 and - C 0-4 alkyl - N(R 11 ) - C(O)R 10 , or, R 13a and R 13b 、R 13c and R 13d together with the carbon atom directly attached to them form C(O), C 3-6 cycloalkyl or a 3 - 6 - membered heterocyclic group;

[0041] R 14 is selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo - substituted C 1-4 alkyl, deuterium - substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3 - 6 - membered heterocyclic group, - C 0-4 alkyl - S(O) r R8, - C 0-4 alkyl - O - R9, - C 0-4 alkyl - C(O)OR9, - C 0-4 alkyl - C(O)R 10 and - C 0-4 alkyl - C(O)NR 11 R 12 ;

[0042] R 15 and R 16 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, 3 - 6 - membered heterocyclic group, C 6-8 aryl, 5 - 8 - membered heteroaryl, - SF5, - S(O) r R8, - O - R9, - C(O)OR9, - C(O)R 10 , - O - C(O)R 10 , - NR 11 R 12 , - C(=NR 11 )R 10 , - N(R 11 ) - C(=NR 12 )R 10 , - C(O)NR 11 R 12 and - N(R 11 ) - C(O)R 10 , or, R 15and R 16 together with the carbon atom directly attached thereto forms a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclic group, said groups being optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, 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, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, ═O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(═NR 11 )R 10 , -N(R 11 )-C(═NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0043] wherein, R8, R9, R 10 , R 11 , R 12 and r are as described for the compound of formula (I).

[0044] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, R2 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, and said groups are independently optionally further substituted by one or more substituents selected from 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, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, ═O, -SF5, -S(O) rR8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 are substituted by the substituents of;

[0045] wherein, R8, R9, R 10 , R 11 , R 12 and r are as described for the compound of formula (I).

[0046] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, R1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, allyl, vinyl, ethynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, hydroxy, C 1-4 alkoxy, C 3-6 cycloalkoxy and 3- to 6-membered heterocyclic oxy group, and the above groups are independently 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 11 R 12 ;

[0047] R 5a , R 5b , R 5c , R 5d and R 5e are each independently 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;

[0048] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl;

[0049] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl;

[0050] wherein, R 11 and R 12 are as described for the compound of formula (I).

[0051] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, R 13a , R 13b , R 13c and R 13d are each independently 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 and C 2-4 alkynyl, or, R 13a and R 13b , R 13c and R 13d together with the carbon atom directly connected thereto form C(O), C 3-6 cycloalkyl or a 3-6 membered heterocyclic group;

[0052] R 14 is selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R8, -C 0-4 alkyl-O-R9, -C(O)OR9, -C(O)R 10 and -C(O)NR 11 R 12 ;

[0053] R 15 and R 16 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, R 15and R 16 Together with the carbon atom directly connected thereto, form a C(O), 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, 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 R8, -O-R9, -C(O)OR9, -C(O)R 10 , -O-C(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;

[0054] Wherein, R8, R9, R 10 , R 11 , R 12 and r are as described for the compound of formula (I).

[0055] 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 the following formula (III):

[0056]

[0057] Wherein, X1 and X2 are each independently N or CH;

[0058] Y is a bond, O, S, N(R 14 ) or C(R 15 R 16 );

[0059] R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, morpholine, 3- to 6-membered oxacyclic group, 3- to 6-membered azacyclic group, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and 3- to 6-membered heterooxacyclic group, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, amino, mono-C 1-4 alkylamino and di-C 1-4 alkylamino;

[0060] R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, 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;

[0061] R 5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 3-6 cycloalkyl;

[0062] R 5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 3-6 cycloalkyl;

[0063] R 14 is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, -S(O) r R8, -C 0-4 alkyl-O-R9, -C(O)OR9, -C(O)R 10 and -C(O)NR 11 R 12 ;

[0064] R 15and R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclic group, or, R 15 and R 16 together with the carbon atom directly attached thereto form a C(O), 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, fluorine, chlorine, bromine, 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, 3-6 membered heterocyclic group, and =O;

[0065] wherein, R8, R9, R 10 , R 11 , R 12 and r are as described for the compound of formula (I).

[0066] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R8 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, and -NR 11 R 12 , and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, 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 11 R 12 ;

[0067] each R9 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8Aryl and 5- to 8-membered heteroaryl, the above groups are each independently 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 11 R 12 ;

[0068] Each R 10 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, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 11 R 12 , and the above groups are each independently 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 11 R 12 ;

[0069] Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxy, 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, mesyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4Alkanoyl, and the above groups are independently 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, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl substituents,

[0070] Alternatively, R 11 and R 12 together with the nitrogen atom directly connected thereto form a 4- to 8-membered heterocyclic group or a 5- to 8-membered heteroaryl, and the 4- to 8-membered heterocyclic group or 5- to 8-membered heteroaryl is 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, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl substituents.

[0071] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, trimethyl-d and dimethyl-d.

[0072] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, morpholine, a 3- to 6-membered oxacyclic group, a 3- to 6-membered azacyclic group, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy and cyclobutoxy, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl;

[0073] R 5a is hydrogen;

[0074] R 5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl and dideuteriomethyl.

[0075] As a further preferred embodiment, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 14 is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl and azetidinyl;

[0076] R 15 and R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, or, R 15 and R 16 together with the carbon atom directly connected thereto form a C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl, and the above groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl and ═O.

[0077] As a most preferred embodiment, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but is not limited to the following compounds:

[0078]

[0079]

[0080] The second aspect of the present invention provides a method for preparing the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:

[0081]

[0082] Wherein, X is chlorine or bromine, and X1, X2, Z, R1, R2, R3, R4, R5, R6 and m are as described in the compound of formula (I).

[0083] The third aspect of the present invention provides a pharmaceutical composition, which comprises a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0084] The present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing at least partially cancers, tumors or metastatic diseases associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0085] The present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and / or treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and disorders of induced cell death. The present invention also relates to the use of the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug 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 partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0086] The present invention also relates to the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, and its acting drug.

[0087] The present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the treatment and / or prevention of at least partially cancers, tumors or metastatic diseases associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0088] The present invention also relates to the use of the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by hyperproliferation and disorders of induced cell death.

[0089] The present invention also relates to the use of the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts for the treatment and / or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, 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 are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0090] The present invention also relates to a method for the treatment and / or prevention of cancers, tumors or metastatic diseases that are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, 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.

[0091] The present invention also relates to a method for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by hyperproliferation 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.

[0092] The present invention also relates to a method for the treatment and / or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, 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 are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, 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

[0093] Through extensive and in-depth research, the inventors of the present application have developed for the first time a pyrimidine-4,6-diamine derivative with the structure of formula (I) below. The series of compounds of the present invention 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 Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, especially drugs for treating hyperproliferative diseases and inducing cell death disorder diseases, and are expected to be developed into a new generation of EGFR inhibitors. On this basis, the present invention has been completed.

[0094] Detailed description: Unless otherwise stated or specifically described, the following terms used in the specification and claims have the following meanings.

[0095] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyls and branched alkyls with 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 its various branched isomers, etc. "C 1-10 alkyl" refers to straight-chain alkyls and branched alkyls including 1 to 10 carbon atoms, "C 1-4 alkyl" refers to straight-chain alkyls and branched alkyls including 1 to 4 carbon atoms, "C 0-8 alkyl" refers to straight-chain alkyls and branched alkyls including 0 to 8 carbon atoms, "C 0-4 alkyl" refers to straight-chain alkyls and branched alkyls including 0 to 4 carbon atoms.

[0096] The alkyl group may be optionally 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(═NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(═NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituted by the substituents.

[0097] "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, "C 3-12 cycloalkyl" refers to cycloalkyl having 3 to 12 carbon atoms, "C 3-6 cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, "C 5-10 cycloalkyl" refers to cycloalkyl having 5 to 10 carbon atoms, "C 5-8 cycloalkyl" refers to cycloalkyl having 5 to 8 carbon atoms, wherein:

[0098] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0099] Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (the spiro atom) is shared between monocyclic rings, which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π - electron system. Spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl according to the number of spiro atoms shared between the rings. Spirocycloalkyl groups include, but are not limited to:

[0100]

[0101] "Fused cycloalkyl" refers to a fully carbonaceous polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π - electron system. Fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl according to the number of constituent rings. Fused cycloalkyl groups include, but are not limited to:

[0102]

[0103] "Bridged cycloalkyl" refers to a fully carbonaceous polycyclic group in which any two rings share two non - directly - connected carbon atoms, which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π - electron system. Bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl according to the number of constituent rings. Bridged cycloalkyl groups include, but are not limited to:

[0104]

[0105] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl, including, but not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

[0106] The cycloalkyl 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, - C0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 and is substituted by substituents of

[0107] "Heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π - electron system. One or more (preferably 1, 2, 3 or 4) ring atoms of the heterocyclic group are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer 0, 1, 2) heteroatoms, but does not include the ring part of -O - O -, -O - S - or -S - S -, and the remaining ring atoms are carbon. Preferably, the heterocyclic group includes 3 to 12 or 3 to 8 or 3 to 6 or 5 to 6 ring atoms. For example, "3 - 6 - membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, "3 - 12 - membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms, "4 - 8 - membered heterocyclic group" refers to a ring group containing 4 to 8 ring atoms, "4 - 10 - membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, "4 - 12 - membered heterocyclic group" refers to a ring group containing 4 to 12 ring atoms, "5 - 6 - membered heterocyclic group" refers to a ring group containing 5 to 6 ring atoms, "5 - 8 - membered heterocyclic group" refers to a ring group containing 5 to 8 ring atoms, "5 - 10 - membered heterocyclic group" refers to a ring group containing 5 to 10 ring atoms.

[0108] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.

[0109] The polycyclic heterocyclic group includes spiro, fused, and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which a single atom (referred to as 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, S(O)(=NH), or S(O) r (where r is an integer of 0, 1, or 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 have a completely conjugated π - electron system. The spiro heterocyclic group is classified into monospiro heterocyclic group, dispiro heterocyclic group, or polyspiro heterocyclic group according to the number of spiro atoms shared between rings. The spiro heterocyclic group includes but is not limited to:

[0110]

[0111] "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. 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 have a completely conjugated π - electron system, and one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH), or S(O) r (where r is an integer of 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. It can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups according to the number of constituent rings. The fused heterocyclic group includes but is not limited to:

[0112]

[0113] "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 have a completely conjugated π - electron system, and one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH), or S(O) r (where r is an integer of 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. It can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups according to the number of constituent rings. The bridged heterocyclic group includes but is not limited to:

[0114]

[0115] The heterocyclic group ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0116]

[0117] The heterocyclic group can be optionally 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(═NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(═NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 and is substituted by the substituents thereof.

[0118] "Aryl" or "aromatic ring" refers to a monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) all-carbon group having a conjugated π-electron system, a polycyclic (i.e., rings having adjacent pairs of carbon atoms) group, preferably an all-carbon aryl containing 6-10 or 6-8 or 6 carbons. For example, "C 6-10 aryl" refers to an all-carbon aryl containing 6-10 carbons, "C 6-8 aryl" refers to an all-carbon aryl containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring can 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:

[0119]

[0120] "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- to 12-membered heteroaryl, C 6-10 aryl, 5- to 10-membered heteroaryl, ═O, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(═NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(═NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituted by the substituents.

[0121] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including heteroatoms such as nitrogen, oxygen, and S(O)r (where r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms. For example, "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to 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:

[0122]

[0123] "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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 and substituted by the substituents thereof.

[0124] "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, and "C 2-4 alkenyl" refers to a straight-chain or branched-chain alkenyl group containing 2-4 carbons. It includes but is not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0125] "Alkenyl" 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, 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituted.

[0126] "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-chain alkynyl group containing 2-10 or 2-4 carbons. For example, "C 2-10 alkynyl" refers to a straight-chain or branched-chain alkynyl group containing 2-10 carbons, and "C 2-4 alkynyl" refers to a straight-chain or branched-chain alkynyl group containing 2-4 carbons. It includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc.

[0127] "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, azido, C 1-10Alkyl, 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, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-O-C(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and is substituted with substituents of

[0128] "Alkoxy" means -O-alkyl, wherein alkyl is as defined above. For example, "C 1-10 alkoxy" means an alkyloxy group having 1 to 10 carbon atoms, and "C 1-4 alkoxy" means an alkyloxy group having 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0129] "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, 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, -C0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-O-C(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 and substituted by substituents of

[0130] "Cyclic alkoxy" means -O-cycloalkyl, where cycloalkyl is defined as above. For example, "C 3-12 cyclic alkoxy" means cycloalkyloxy containing 3-12 carbons, and "C 3-8 cyclic alkoxy" means cycloalkyloxy containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.

[0131] "Cyclic alkoxy" 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, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O) r R8, -C 0-8 alkyl-O-R9, -C 0-8 alkyl-C(O)OR9, -C 0-8 alkyl-C(O)R10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 substituted by a substituent.

[0132] "Heterocyclyloxy" refers to an -O-heterocyclyl group, wherein heterocyclyl is as defined above, and heterocyclyloxy includes, but is not limited to, azetidinyloxy, oxetanyloxy, azepanyloxy, nitrogen, oxhexyloxy, and the like.

[0133] "Heterocyclyloxy" 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, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11)-C(=NR 12 )R 10 、-C 0-8 alkyl - C(O)NR 11 R 12 and - C 0-8 alkyl - N(R 11 ) - C(O)R 10 is substituted by the substituents of.

[0134] “C 1-10 alkanoyl” means the monovalent group remaining after removing the hydroxyl group from C 1-10 alkyl acid, and is usually also represented as “C 0-9 alkyl - C(O)-”. For example, “C1 alkyl - C(O)-” refers to acetyl; “C2 alkyl - C(O)-” refers to propionyl; “C3 alkyl - C(O)-” refers to butyryl or isobutyryl.

[0135] “C 1-4 ” means “C 1-4 alkyl”, “C 0-4 ” means “C 0-4 alkyl”, “C 1-8 ” means C 1-8 alkyl, “C 0-8 ” means C 0-8 alkyl, as defined above.

[0136] “ - C 0-8 alkyl - S(O) r R8” means that the sulfur atom in - S(O) r R8 is connected to C 0-8 alkyl, and the definition of C 0-8 alkyl is as described above.

[0137] “ - C 0-8 alkyl - O - R9” means that the oxygen atom in - O - R9 is connected to C 0-8 alkyl, and the definition of C 0-8 alkyl is as described above.

[0138] “ - C 0-8 alkyl - C(O)OR9” means that the carbonyl group in - C(O)OR9 is connected to C 0-8 alkyl, and the definition of C 0-8 alkyl is as described above.

[0139] “ - C 0-8 alkyl - C(O)R 10 ” means that the carbonyl group in - C(O)R 10 is connected to C 0-8 alkyl, and the definition of C 0-8 alkyl is as described above.

[0140] “-C 0-8 alkyl - O - C(O)R 10 ” means - O - C(O)R 10 wherein the oxygen atom is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0141] “-C 0-8 alkyl - NR 11 R 12 ” means - NR 11 R 12 wherein the nitrogen atom is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0142] “-C 0-8 alkyl - C(=NR 11 )R 10 ” means - C(=NR 11 )R 10 wherein the carbon atom is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0143] “-C 0-8 alkyl - N(R 11 ) - C(=NR 12 )R 10 ” means - N(R 11 ) - C(=NR 12 )R 10 wherein the nitrogen atom is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0144] “-C 0-8 alkyl - C(O)NR 11 R 12 ” means - C(O)NR 11 R 12 wherein the carbonyl group is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0145] “-C 0-8 alkyl - N(R 11 ) - C(O)R 10 ” means - N(R 11 ) - C(O)R 10 wherein the nitrogen atom is connected to C 0-8 alkyl, and C 0-8 alkyl is defined as above.

[0146] "Halogen-substituted C 1-10 alkyl" refers to a C1-C10 alkyl group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl (-CHF2), dichloromethyl (-CHCl2), dibromomethyl (-CHBr2), trifluoromethyl (-CF3), trichloromethyl (-CCl3), tribromomethyl (-CBr3), etc.

[0147] "Halogen-substituted C 1-10 alkoxy" refers to a C1-C10 alkoxy group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms. It includes but is not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.

[0148] "Deuterium-substituted C 1-10 alkyl" refers to a C1-C10 alkyl group in which the hydrogen on the alkyl group is optionally substituted by deuterium atoms. It includes but is not limited to monodeuteriomethyl (-CH2D), dideuteriomethyl (-CHD2), trideuteriomethyl (-CD3), etc.

[0149] "Deuterium-substituted C 1-10 alkoxy" refers to a C1-C10 alkoxy group in which the hydrogen on the alkyl group is optionally substituted by deuterium atoms. It includes but is not limited to monodeuteriomethoxy, dideuteriomethoxy, trideuteriomethoxy, etc.

[0150] "Halogen" refers to fluorine, chlorine, bromine or iodine. "EtOAc" refers to ethyl acetate. "PE" refers to petroleum ether. "DMF" refers to dimethylformamide. "DMSO" refers to dimethyl sulfoxide.

[0151] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur, that is, it includes both the substituted and unsubstituted cases. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0152] "Substituted" means that one or more "hydrogen atoms" in the group are independently substituted 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 theory, and those skilled in the art can determine (by experiment or theory) what is possible or impossible to substitute without too 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).

[0153] "Stereoisomer", whose English name is stereoisomer, refers to the isomers generated by the different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or can be divided into two major categories: enantiomers and diastereoisomers. The stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. The 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 the configuration stereo-isomers are divided into two categories. Among them, the isomers caused by the inability of the double bond or the single bond of the ring-forming carbon atom 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. If the compounds of the present invention contain double bonds, unless otherwise specified, they can be understood to contain E and / or Z configurations. The 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 R and S configurations. In the present invention, the "stereoisomer" can be understood to contain one or several of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.

[0154] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, and these salts can be prepared by methods known in the art.

[0155] "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 biological activity.

[0156] 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.

[0157] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is carried out with a Bruker AVANCE-400 / 500 nuclear magnetic resonance instrument, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (MeOH-d4) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0158] For the determination by liquid chromatography-mass spectrometry (LC-MS), an Agilent 6120 mass spectrometer was used. For the determination by HPLC, an Agilent 1200 DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm chromatographic column) were used.

[0159] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specification for TLC was 0.15 mm - 0.20 mm, and the specification for separating and purifying products by thin-layer chromatography was 0.4 mm - 0.5 mm. For column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai was generally used as the carrier.

[0160] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.

[0161] Unless otherwise specified, all reactions of the present invention were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was a dry solvent, and the reaction temperature unit was degrees Celsius (°C).

[0162] I. Preparation of intermediates

[0163] Intermediate 1: Preparation of 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0164]

[0165] First step: Synthesis of 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0166]

[0167] 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.2 g, 6.48 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (1.43 g, 7.77 mmol) and K2CO3 (1.79 g, 12.96 mmol) were placed in DMSO (25 mL). Under nitrogen protection, it was stirred at 80 °C overnight. The reaction solution was diluted with water, then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration, it was separated by column chromatography to obtain 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (2.15 g, yield: 95.2%). MS m / z (ESI): 349.2 [M+H] +。

[0168] Step 2: Synthesis of 2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0169]

[0170] 1-(1-(5-Methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1 g, 2.87 mmol) and Pd / C (50 mg, 10%) were placed in methanol (30 mL), purged with hydrogen gas, and then stirred at room temperature for 1 hour under an atmosphere of hydrogen gas at atmospheric pressure. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (900 mg, yield: 98.5%). MS m / z (ESI): 319.2 [M+H] + 。

[0171] Intermediate 2: Preparation of 2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline

[0172]

[0173] Step 1: Synthesis of 4-(1-(5-Methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine

[0174]

[0175] 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.73 g, 3.94 mmol) was added to DMSO (20 mL), followed by the addition of K2CO3 (1.09 g, 7.89 mmol) and 4-(piperidin-4-yl)morpholine (0.81 g, 4.73 mmol). The reaction was carried out at 80 °C overnight and then heated to 110 °C for 5 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography [eluent: CH2Cl2 / MeOH (+1% ammonia) = 0 - 10%] to obtain 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine (1.23 g, yield: 80.9%). MS m / z (ESI): 336.0 [M+H] + 。

[0176] Step 2: Synthesis of 2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline

[0177]

[0178] 4-(1-(5-Methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine (1.23 g, 3.18 mmol) was dissolved in methanol (10 mL), and then Pd / C (0.10 g, 10%) was added. After replacing the hydrogen three times, the reaction was carried out at room temperature overnight under an atmosphere of hydrogen at normal pressure. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product obtained was separated by column chromatography [eluent: CH2Cl2 / MeOH (+1% ammonia water) = 0 - 10%] to obtain 2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.81 g, yield: 80.2%). MS m / z (ESI): 306.2 [M+H] + 。

[0179] Intermediate 3: Preparation of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0180]

[0181] The first step: Synthesis of 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene

[0182]

[0183] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), and then K2CO3 (969.16 mg, 7.01 mmol) and iodoethane (0.37 mL, 4.68 mmol) were added, and the mixture was stirred overnight. After the reaction was completed, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, yield: 90.2%) was obtained. MS m / z (ESI): 200 [M+H] + 。

[0184] The second step: Synthesis of 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0185]

[0186] 1-Ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, 2.11 mmol) was dissolved in DMSO (10 mL), then K2CO3 (582 mg, 4.22 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (580 mg, 3.16 mmol) were added, and the mixture was stirred overnight at 90 °C. After the reaction was completed, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (700 mg, yield: 91.6%). MS m / z (ESI): 363 [M+H] + 。

[0187] Step 3: Synthesis of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0188]

[0189] 1-(1-(5-Ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (700 mg, 1.93 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1.03 g, 19.31 mmol) and Fe powder (1.08 g, 19.31 mmol) were added, and the mixture was stirred at 85 °C for 2 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (610 mg, yield: 95%). MS m / z (ESI): 333.2 [M+H] + 。

[0190] Intermediate 4: Preparation of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0191]

[0192] Step 1: Synthesis of 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene

[0193]

[0194] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), Na2CO3 (743 mg, 7.01 mmol) was added, the reaction solution was heated to 90 °C, and then ClCF2CO2Na (1247 mg, 8.18 mmol) was added. The reaction was stirred at 90 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, yield: 92.9%). MS m / z (ESI): 222.0 [M+H] + 。

[0195] Step 2: Synthesis of 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0196]

[0197] 1-(Difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, 2.17 mmol) was dissolved in DMSO (10 mL), then K2CO3 (750 mg, 5.43 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (597 mg, 3.26 mmol) were added, and the mixture was stirred at 90 °C overnight. After the reaction was completed, it was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (760 mg, yield: 91.1%). MS m / z (ESI): 385.0 [M+H] + 。

[0198] Step 3: Synthesis of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0199]

[0200] 1-(1-(5-(Difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (760 mg, 1.98 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1057 mg, 19.77 mmol) and Fe powder (1104 mg, 19.77 mmol) were added, and the mixture was stirred at 85 °C for 2 h. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (310 mg, yield: 44.2%). MS m / z (ESI): 355.0 [M+H] + 。

[0201] Intermediate 5: Preparation of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline

[0202]

[0203] First step: Synthesis of 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene

[0204]

[0205] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (15 mL), then K2CO3 (969 mg, 7.01 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.67 mL, 4.68 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (560 mg, yield: 94.6%). MS m / z (ESI): 254.0 [M+H] + 。

[0206] Second step: Synthesis of 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine

[0207]

[0208] 1-Fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (580 mg, 2.29 mmol) was dissolved in DMSO (15 mL), and K2CO3 (792 mg, 5.73 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (630 mg, 3.44 mmol) were added. The mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine (900 mg, yield: 94.3%). MS m / z (ESI): 417.0 [M+H] + 。

[0209] Step 3: Synthesis of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline

[0210]

[0211] 1-Methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine (900 mg, 2.16 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1156 mg, 21.61 mmol) and Fe powder (1207 mg, 21.61 mmol) were added. The mixture was stirred at 85 °C for 2 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (780 mg, yield: 93.4%). MS m / z (ESI): 387.0 [M+H] + 。

[0212] Intermediate 6: Preparation of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0213]

[0214] Step 1: Synthesis of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0215]

[0216] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.40 g, 5.60 mmol) was dissolved in dimethylamine (10.0 mL), and then K2CO3 (1.55 g, 11.20 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.54 g, 8.40 mmol) were added. The mixture was heated at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, dichloromethane and water were added to the reaction solution for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography to obtain 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (2.20 g, yield: 92.9%). MS m / z (ESI): 413.0, 415.0 [M+H] + 。

[0217] Step 2: Synthesis of 1-(1-(5-methoxy-4-nitro-2-ethenylphenyl)piperidin-4-yl)-4-methylpiperazine

[0218]

[0219] 1-(1-(2-Bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (400 mg, 0.97 mmol) was dissolved in 1,4-dioxane (16 mL) and water (4 mL), and then potassium vinyltrifluoroborate (259 mg, 1.94 mmol), Na2CO3 (308 mg, 2.90 mmol) and Pd(dppf)Cl2 (70.8 mg, 0.10 mmol) were added. The mixture was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-4-nitro-2-ethenylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, yield: 86.0%). MS m / z (ESI): 361.0 [M+H] + 。

[0220] Step 3: Synthesis of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0221]

[0222] Dissolve 1-(1-(5-methoxy-4-nitro-2-ethenylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, 0.83 mmol) in methanol (20 mL), then add Pd / C (30 mg, 10%), and stir at room temperature for 2 hours under an atmosphere of normal pressure hydrogen. After the reaction is completed, filter, concentrate the filtrate, and separate the crude product by column chromatography to obtain 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (200 mg, yield: 72.3%). MS m / z (ESI): 333.2 [M+H] + 。

[0223] Intermediate 7: Preparation of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0224]

[0225] First step: Synthesis of 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidin-4-yl)-4-methylpiperazine

[0226]

[0227] Place 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) in 1,4-dioxane (10 mL) and water (3 mL), then add Na2CO3 (0.30 g, 2.83 mmol), Pd(dppf)Cl2 (0.03 g, 0.05 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.20 mL, 1.04 mmol), and react at 90 °C overnight under nitrogen protection. Cool the reaction solution to room temperature, add ethyl acetate and water for extraction. Wash the organic phase with saturated brine and dry over sodium sulfate. Filter, concentrate, and separate the crude product by column chromatography to obtain 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidin-4-yl)-4-methylpiperazine (0.26 g, yield: 61.0%). MS m / z (ESI): 375.2 [M+H] + 。

[0228] Second step: Synthesis of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0229]

[0230] 1-(1-(5-Methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidin-4-yl)-4-methylpiperazine (0.26 g, 0.57 mmol) was dissolved in methanol (10 mL), and Pd / C (0.05 g, 10%) was added. The reaction was carried out at room temperature for 3 hours under an atmosphere of hydrogen at atmospheric pressure. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The obtained crude product was separated by column chromatography [developing agent: CH2Cl2 / MeOH (+1% aqueous ammonia) = 0 - 10%] to obtain 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.14 g, yield: 67.7%). MS m / z (ESI): 347.2 [M+H] + 。

[0231] Intermediate 8: Preparation of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0232]

[0233] First step: Synthesis of 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0234]

[0235] To a solution of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) in toluene (10 mL), K3PO4 (0.60 g, 2.83 mmol), tricyclohexylphosphine (0.079 g, 0.28 mmol), Pd(OAc)2 (0.03 g, 0.14 mmol), and cyclopropylboronic acid (0.24 g, 2.83 mmol) were added. The reaction was carried out at 120 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, and ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.28 g, yield: 68.5%). MS m / z (ESI): 375.2 [M+H] + 。

[0236] Second step: Synthesis of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0237]

[0238] 1-(1-(2-Cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.28 g, 0.65 mmol) was dissolved in a mixture of methanol (8 mL) and water (2 mL). Then, Fe powder (0.18 g, 3.23 mmol) and NH4Cl (0.35 g, 6.47 mmol) were added. The reaction was heated at 70 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated. The crude product obtained was separated by column chromatography to give 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.21 g, yield: 89.2%). MS m / z (ESI): 345.2 [M+H] + 。

[0239] Intermediate 9: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoaniline

[0240]

[0241] First step: Synthesis of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole

[0242]

[0243] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (900 mg, 3.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.12 g, 5.4 mmol), K2CO3 (1.49 g, 10.8 mmol), and Pd(dppf)Cl2 (263 mg, 0.36 mmol) were placed in 1,4-dioxane (15 mL) and water (3 mL). Under nitrogen protection, the mixture was heated at 100 °C and stirred overnight. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the crude product was separated by column chromatography to give 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (900 mg, yield: 99.5%). MS m / z (ESI): 252.1 [M+H] + 。

[0244] Second step: Synthesis of 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)morpholine

[0245]

[0246] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (150 mg, 0.60 mmol), K2CO3 (247.6 mg, 1.80 mmol), and morpholine (104 mg, 1.19 mmol) were placed in DMSO (10 mL). Under nitrogen protection, the mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)morpholine (160 mg, yield: 84.2%). MS m / z (ESI): 319.1 [M+H] + 。

[0247] Step 3: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoaniline

[0248]

[0249] 4-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)morpholine (160 mg, 0.52 mmol) was placed in methanol (10 mL), and 10% Pd / C (20 mg) was added. The mixture was stirred at room temperature for 30 minutes under an atmosphere of hydrogen at atmospheric pressure. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoaniline (106 mg, yield: 68.3%). MS m / z (ESI): 289.1 [M+H] + 。

[0250] Intermediate 10: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline

[0251]

[0252] Step 1: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-methylpiperazine

[0253]

[0254] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (150 mg, 0.60 mmol), K2CO3 (248 mg, 1.80 mmol), and N-methylpiperazine (119 mg, 1.19 mmol) were placed in DMSO (10 mL), and the mixture was heated to 100 °C and stirred overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, yield: 75.8%). MS m / z (ESI): 332.1 [M+H] + 。

[0255] Step 2: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline

[0256]

[0257] 1-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, 0.45 mmol) was placed in methanol (10 mL), and 10% Pd / C (20 mg) was added. The mixture was stirred at room temperature for 30 minutes under an atmosphere of hydrogen at atmospheric pressure. The reaction solution was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline (68 mg, yield: 50.3%). MS m / z (ESI): 302.1 [M+H] + 。

[0258] Intermediate 11: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0259]

[0260] Step 1: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0261]

[0262] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.30 g, 1.19 mmol) was dissolved in dimethylamine (5 mL), and then K2CO3 (0.50 g, 3.58 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (0.88 g, 4.78 mmol) were added. The mixture was heated at 100 °C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.23 g, yield: 44.7%). MS m / z (ESI): 415.2 [M+H] + 。

[0263] Step 2: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0264]

[0265] 1-(1-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.23 g, 0.53 mmol) was placed in methanol (10 mL), 10% Pd / C (0.10 g) was added, the gas was replaced with hydrogen, and the reaction was carried out at room temperature overnight under an atmospheric hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.16 g, yield: 72.7%). MS m / z (ESI): 385.2 [M+H] + 。

[0266] Intermediate 12: Preparation of 5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0267]

[0268] Step 1: Synthesis of 4,5-difluoro-2-methoxy-1-nitrobenzene

[0269]

[0270] Under ice bath cooling, 1,2-difluoro-4-methoxybenzene (1.626 mL, 13.88 mmol) was added to concentrated H2SO4 (6.81 g, 69.39 mmol) at 0 °C, and then concentrated HNO3 (1.37 g, 15.27 mmol) was slowly added dropwise. After the addition, the reaction was carried out at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into ice water and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and saturated NaCl solution. The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and the crude product was separated by silica gel column chromatography to obtain 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol, yield: 43.3%).

[0271] Step 2: Synthesis of 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine

[0272]

[0273] To a solution of 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol) in 1,4-dioxane (10 mL) were added 1-methyl-4-(piperidin-4-yl)piperazine (1.10 g, 6.00 mmol) and DIPEA (1.94 g, 14.99 mmol). The mixture was heated to 100 °C and stirred under N2 protection for 2 hours. After the reaction was complete, it was cooled to room temperature. After the reaction solution was concentrated, the crude product 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine was obtained and directly used in the next step of the reaction.

[0274] Step 3: Synthesis of 5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0275]

[0276] To the crude product of 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridin-4-yl)-4-methylpiperazine (2.26 g, 5.99 mmol) were added methanol (8 mL) and water (2 mL), followed by Fe powder (1.67 g, 29.95 mmol) and NH4Cl (3.20 g, 59.90 mmol). Under N2 protection, the mixture was heated to 75 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated, the residue was added with ammonia water, and then extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and separated by silica gel column chromatography to obtain 5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl)aniline (1.44 g, 4.42 mmol, yield: 73.9%). MS m / z (ESI): 323.2 [M+H] + 。

[0277] Intermediate 13: Preparation of 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0278]

[0279] It was synthesized from 1-chloro-2-fluoro-4-methoxybenzene with reference to the preparation method of Intermediate 12. MS m / z (ESI): 339.2 [M+H] + 。

[0280] Intermediate 14: Preparation of 2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0281]

[0282] It was prepared from 1,4-dichloro-2-fluorobenzene with reference to the preparation method of Intermediate 12. MS m / z (ESI): 343.2 [M+H] + 。

[0283] Intermediate 15: Preparation of 2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline

[0284]

[0285] It was prepared from 1-chloro-5-fluoro-4-methyl-2-nitrobenzene with reference to the preparation method of Intermediate 1. MS m / z (ESI): 323.2 [M+H] + 。

[0286] Preparation of Intermediate 16: 4-(4-(4-Ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylaniline

[0287]

[0288] Prepared according to the preparation method of Intermediate 1. MS m / z(ESI): 333.2 [M+H] + 。

[0289] II. Preparation of Specific Examples

[0290] Example 1: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine Preparation

[0291]

[0292] First Step: Synthesis of 2-(2-Fluorophenyl)pyridin-4-amine

[0293]

[0294] 2-Bromopyridin-4-amine (10 g, 57.80 mmol) and (2-fluorophenyl)boronic acid (9.70 g, 69.36 mmol) were dissolved in 1,4-dioxane (170 mL), and then aqueous Na2CO3 solution (2 M, 86.7 mL, 173.40 mmol) and Pd(PPh3)4 (1.34 g, 1.16 mmol) were added. After the reaction solution was purged with nitrogen three times, the temperature was raised to 90 °C and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature, saturated brine (600 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography [eluent: EtOAc / PE = 0 - 50%] to obtain 2-(2-fluorophenyl)pyridin-4-amine (10.0 g, yield: 92%). MS m / z(ESI): 189.0 [M+H] + 。

[0295] Second Step: Synthesis of 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine

[0296]

[0297] 2-(2-Fluorophenyl)pyridin-4-amine (5 g, 26.57 mmol) was placed in DMF (50 mL), and 60% NaH (1.59 g, 39.85 mmol) was added under cooling in an ice-water bath. The mixture was stirred at room temperature for 1 hour, and then 4,6-dichloropyrimidine (4.75 g, 31.88 mmol) was added under cooling in an ice-water bath. Then the mixture was stirred overnight at room temperature. The reaction solution was quenched with ethanol and concentrated. The crude product was separated by column chromatography to obtain 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (1 g, yield: 12.5%). MS m / z (ESI): 301.2 [M+H] + 。

[0298] Step 3: Synthesis of N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine

[0299]

[0300] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (50 mg, 0.17 mmol) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (63.5 mg, 0.2 mmol) were added to ethylene glycol monomethyl ether (3 mL), and then 4M HCl / dioxane solution (0.17 mL, 0.67 mmol) was added. The mixture was stirred at 120 °C overnight. The reaction solution was neutralized with NH3 / MeOH solution, concentrated, and separated by reverse-phase column chromatography to obtain N[[ID=??]] 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (21.5 mg, yield: 22.9%). MS m / z (ESI): 583.2 [M+H] + 。

[0301] 1 It seems there might be an issue with the "??" marked item in the original text where the tag 4 is repeated in the translation. Please check and correct if necessary.1H NMR (400 MHz, MeOH-d4) δ 8.27 (d, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.64 - 6.59 (m, 2H), 7.39 - 7.33 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.15 - 7.09 (m, 2H), 6.66 (s, 1H), 5.95 (s, 1H), 3.72 (s, 3H), 3.08 (d, J = 11.9 Hz, 2H), 2.65 - 2.53 (m, 6H), 2.48 - 2.41 (m, 4H), 2.31 - 2.5 (m, 1H), 2.22 (s, 3H), 2.14 (s, 3H), 1.94 - 1.88 (m, 2H), 1.65 - 1.56 (m, 2H).

[0302] Example 2: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -Preparation of -(2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)phenyl)pyrimidine-4,6-diamine

[0303]

[0304] 2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.24 g, 0.76 mmol) and 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (0.20 g, 0.64 mmol) were placed in tert-butanol (10 mL), and then p-toluenesulfonic acid monohydrate (0.60 g, 3.18 mmol) was added. The mixture was heated at 100 °C for 36 hours. The reaction solution was cooled to room temperature, neutralized with ammonia water, concentrated, and the crude product was separated by column chromatography to obtain N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)phenyl)pyrimidine-4,6-diamine (80 mg, yield: 41.1%). MS m / z (ESI): 570.2 [M+H] + .

[0305] 1HNMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.2 Hz, 1H), 7.52 - 7.41 (m, 1H), 7.36 - 7.26 (m, 2H), 7.21 (s, 1H), 6.72 (s, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 3.59 (t, J = 4.6 Hz, 4H), 3.11 (d, J = 11.5 Hz, 2H), 2.92 (s, 2H), 2.64 (t, J = 11.5 Hz, 2H), 2.35 - 2.21 (m, 2H), 2.17 (s, 3H), 1.99 (dt, J = 13.2, 7.0 Hz, 1H), 1.89 (d, J = 11.6 Hz, 2H), 1.64 - 1.49 (m, 2H).

[0306] Example 3: N 4 -(2-Ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -Preparation of (2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine

[0307]

[0308] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine (180 mg, 0.60 mmol) and 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (219 mg, 0.66 mmol), NaO t Bu (115 mg, 1.20 mmol) and BrettPhos Pd-G3 (109 mg, 0.12 mmol) were placed in toluene (10 mL). Under nitrogen protection, it was heated to 90 °C and stirred overnight. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. The crude product was further separated by a preparative column to obtain N 4 -(2-Ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (65 mg, yield: 18.0%). MS m / z (ESI): 597.3 [M + H] + .

[0309] 11H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.28 (d, J = 15.0 Hz, 2H), 7.99 (s, 1H), 7.91 (td, J = 7.9, 1.8 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.37 - 7.26 (m, 2H), 7.17 (s, 1H), 6.70 (s, 1H), 5.91 (s, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.43 - 3.38 (m, 2H), 3.09 (d, J = 11.4 Hz, 2H), 2.61 (t, J = 11.5 Hz, 4H), 2.39 - 2.26 (m, 5H), 2.16 (s, 3H), 2.15 (s, 3H), 1.85 (d, J = 11.8 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.24 (t, J = 6.9 Hz, 3H).

[0310] Example 4: N 4 -(2-(Difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine Preparation

[0311]

[0312] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (200 mg, 0.67 mmol) and 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (259 mg, 0.73 mmol), NaO t Bu (128 mg, 1.33 mmol) and BrettPhos Pd-G3 (121 mg, 0.13 mmol) were placed in toluene (10 mL). Under nitrogen protection, the mixture was stirred at 90 °C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. Then it was separated by a preparative column to obtain N 4 -(2-(Difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (25 mg, Yield: 6.1%). MS m / z (ESI): 619.3 [M + H] + .

[0313] 11H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.65 (s, 1H), 8.44 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.36 - 7.26 (m, 3H), 7.21 (s, 0.25H), 7.03 (s, 0.5H), 6.84 (d, J = 3.2 Hz, 1.25H), 5.98 (s, 1H), 3.11 (d, J = 11.4 Hz, 2H), 2.59 (td, J = 11.9, 2.2 Hz, 4H), 2.41 - 2.26 (m, 5H), 2.22 (s, 3H), 2.15 (s, 3H), 1.86 (d, J = 11.0 Hz, 2H), 1.64 - 1.52 (m, 2H).

[0314] Example 5: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(5-Methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrimidine-4,6-diamine Preparation

[0315]

[0316] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (53 mg, 0.18 mmol) and 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (68 mg, 0.18 mmol), NaO t Bu (34 mg, 0.35 mmol) and BrettPhos Pd-G3 (16 mg, 0.02 mmol) were placed in toluene (10 mL). Under nitrogen protection, it was stirred at 90 °C overnight. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the crude product was obtained by column chromatography, and then separated by a preparative column to obtain N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(5-Methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrimidine-4,6-diamine (1.2 mg, yield: 1%). MS m / z (ESI): 651.4 [M + H] + .

[0317] 11H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.43 (t, J = 2.8 Hz, 2H), 8.25 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.91 (td, J = 7.9, 2.0 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (td, J = 5.6, 2.6 Hz, 1H), 7.31 (dd, J = 9.3, 6.9 Hz, 2H), 7.16 (s, 1H), 6.84 (s, 1H), 5.88 (s, 1H), 4.68 (q, J = 8.9 Hz, 2H), 3.11 (d, J = 11.5 Hz, 2H), 2.92 (s, 2H), 2.68 - 2.60 (m, 3H), 2.39 - 2.27 (m, 6H), 2.18 (s, 3H), 2.15 (s, 3H), 2.05 - 1.94 (m, 2H), 1.86 (d, J = 12.1 Hz, 2H), 1.64 - 1.53 (m, 2H).

[0318] Example 6: N 4 -(5-Ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine Preparation

[0319]

[0320] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.33 mmol) and 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (122 mg, 0.37 mmol), NaO t Bu (63.9 mg, 0.67 mmol) and BrettPhos Pd-G3 (60.3 mg, 0.07 mmol) were placed in toluene (10 mL). Under nitrogen protection, the mixture was stirred at 90 °C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. The crude product was further separated by a preparative column to obtain N 4 -(5-Ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (38 mg, yield: 19.2%). MS m / z (ESI): 597.3 [M + H] + .

[0321] 11H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.47 - 8.36 (m, 2H), 8.26 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.6, 2.1 Hz, 1H), 7.51 - 7.41 (m, 1H), 7.37 - 7.27 (m, 2H), 7.23 (s, 1H), 6.78 (s, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 3.29 - 3.23 (m, 2H), 3.03 (d, J = 11.3 Hz, 2H), 2.71 - 2.64 (m, 2H), 2.57 (q, J = 7.5 Hz, 4H), 2.38 - 2.25 (m, 5H), 2.15 (s, 3H), 1.85 (d, J = 11.7 Hz, 2H), 1.61 - 1.51 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0322] Example 7: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(5-Isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine Preparation

[0323]

[0324] To a solution of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.14 g, 0.39 mmol) in toluene (10 mL) was added 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (0.12 g, 0.39 mmol), BrettPhos Pd-G3 (0.04 g, 0.04 mmol), and NaO t Bu (0.07 g, 0.77 mmol). The reaction mixture was heated at 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The resulting crude product was further separated by a preparative column to obtain N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(5-Isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (50.5 mg, yield: 21.3%). MS m / z (ESI): 611.4 [M + H] + .

[0325] 1HNMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.43 (d, J = 4.6 Hz, 2H), 8.26 (s, 1H), 7.98 (s, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.73 (d, J = 4.4 Hz, 1H), 7.46 (q, J = 6.9 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.26 (s, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 3.76 (s, 3H), 2.98 (d, J = 11.1 Hz, 2H), 2.71 (t, J = 11.6 Hz, 2H), 2.32 (s, 5H), 2.15 (s, 3H), 1.85 (d, J = 11.9 Hz, 2H), 1.64 - 1.50 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H).

[0326] Example 8: N 4 -(5-Cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine Preparation

[0327]

[0328] To a solution of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.20 g, 0.55 mmol) in toluene (10 mL), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (0.16 g, 0.49 mmol), BrettPhos Pd-G3 (0.05 g, 0.06 mmol), and NaO t Bu (0.11 g, 1.10 mmol) were added. The reaction was heated at 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The obtained crude product was further separated by a preparative column to obtain N 4 -(5-Cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (96.8 mg, yield: 28.8%). MS m / z (ESI): 609.4 [M + H] + .

[0329] 1HNMR(400MHz, DMSO-d6) δ 9.58 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (tdd, J = 7.7, 5.1, 1.9 Hz, 1H), 7.36 - 7.26 (m, 2H), 6.78 (s, 1H), 6.71 (s, 1H), 5.83 (s, 1H), 3.75 (s, 3H), 2.67 (t, J = 11.2 Hz, 2H), 2.41 - 2.23 (m, 5H), 2.19 - 2.07 (m, 4H), 1.87 (d, J = 11.7 Hz, 2H), 1.67 - 1.54 (m, 2H), 0.97 - 0.87 (m, 2H), 0.63 - 0.54 (m, 2H).

[0330] Example 9: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine Preparation

[0331]

[0332] To a solution of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.16 g, 0.39 mmol) in toluene (10 mL), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine (0.12 g, 0.39 mmol), BrettPhos Pd-G3 (0.06 g, 0.07 mmol), and NaO t Bu (0.07 g, 0.78 mmol) were added. The reaction mixture was heated at 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The obtained crude product was further separated by a preparative column to obtain N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (65 mg, Yield: 25.2%). MS m / z (ESI): 649.4 [M + H] + .

[0333] 1 HNMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.45 - 8.39 (m, 2H), 8.26 (d, J = 0.8 Hz, 1H), 8.06 (s, 1H), 7.99 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 8.0, 1.9 Hz, 1H), 7.87 (s, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.36 - 7.25 (m, 2H), 6.80 (s, 1H), 5.93 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.12 (d, J = 11.1 Hz, 2H), 2.63 - 2.53 (m, 4H), 2.39 - 2.27 (m, 4H), 2.26 - 2.19 (m, 1H), 2.15 (s, 3H), 1.82 (d, J = 11.5 Hz, 2H), 1.61 - 1.48 (m, 2H).

[0334] Example 10: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -Preparation of -(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine

[0335]

[0336] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine (100 mg, 0.33 mmol) and 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoaniline (106 mg, 0.37 mmol), NaO t Bu (64 mg, 0.67 mmol) and BrettPhos Pd-G3 (30 mg, 0.03 mmol) were placed in toluene (15 mL). Under nitrogen protection, the mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was further separated by a preparative column to obtain N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine (40.5 mg, yield: 22.0%). MS m / z (ESI): 553.2 [M + H] + .

[0337] 11H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.46 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.75 - 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.34 - 7.28 (m, 2H), 6.83 (s, 1H), 5.96 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.75 - 3.72 (m, 4H), 2.87 - 2.83 (m, 4H).

[0338] Example 11: N 4 -(2-(2-Fluorophenyl)pyridin-4-yl)-N 6 -Preparation of -(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-4,6-diamine

[0339]

[0340] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (62 mg, 0.21 mmol) and 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline (68 mg, 0.23 mmol), NaO t Bu (40 mg, 0.41 mmol) and BrettPhos Pd-G3 (18 mg, 0.02 mmol) were placed in toluene (10 mL). Under nitrogen protection, the mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was further separated by a preparative column to obtain N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-4,6-diamine (25.5 mg, yield: 21.9%). MS m / z (ESI): 566.2 [M + H] + .

[0341] 11H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.47 - 8.40 (m, 2H), 8.27 (s, 1H), 8.06 (s, 1H), 7.99 (t, J = 2.0 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.74 - 7.72 (dd, J = 5.7, 2.2 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.33 - 7.28 (m, 2H), 6.81 (s, 1H), 5.94 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.88 - 2.84 (m, 4H), 2.48 - 2.41 (m, 4H), 2.24 (s, 3H).

[0342] Example 12: N 4 -(5-(2-Fluorophenyl)pyridin-3-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine Preparation

[0343]

[0344] Step 1: Synthesis of 5-(2-Fluorophenyl)pyridin-3-amine

[0345]

[0346] Refer to the operation of Step 1 in Example 1.

[0347] Step 2: N 4 -(5-(2-Fluorophenyl)pyridin-3-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine Synthesis

[0348]

[0349] Dissolve 4,6-dichloropyrimidine (60 mg, 0.40 mmol), 5-(2-fluorophenyl)pyridin-3-amine (76 mg, 0.40 mmol), and 2-methoxy-5-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (130 mg, 0.40 mmol) in anhydrous 1,4-dioxane (8 mL). Under nitrogen protection, add BrettPhos Pd-G3 (37 mg, 0.04 mmol) and NaO t Bu (77 mg, 0.81 mmol), and heat at 85 °C overnight. Cool the reaction solution to room temperature, concentrate, and separate by column chromatography. The crude product is further separated by high-performance liquid chromatography column to obtain N 4-(5-(2-Fluorophenyl)pyridin-3-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (14 mg, yield: 6.1%). MS m / z (ESI): 583.2 [M+H] + 。

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.30 - 8.26 (m, 2H), 8.24 (s, 1H), 8.18 (s, 1H), 7.57 (td, J = 7.8, 1.8 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.44 - 7.29 (m, 2H), 7.21 (s, 1H), 6.70 (s, 1H), 5.85 (s, 1H), 3.75 (s, 3H), 3.09 (d, J = 11.3 Hz, 2H), 2.63 (t, J = 11.4 Hz, 3H), 2.37 - 2.25 (m, 5H), 2.16 (s, 3H), 2.15 (s, 3H), 1.86 (d, J = 11.9 Hz, 2H), 1.67 - 1.47 (m, 2H).

[0351] Example 13: N 4 -(5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -Preparation of -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine

[0352]

[0353] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (101.6 mg, 0.338 mmol) and 5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (100 mg, 0.307 mmol) were dissolved in 2-butanol (2.0 mL), TFA (0.4 mL, 5.385 mmol) was added, and the mixture was heated at 130 °C overnight in a sealed tube under N2 protection. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain N 4 -(5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6-(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (35.0 mg, 0.060 mmol, yield: 19.3%). MS m / z (ESI): 587.2 [M+H] + 。

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.55 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.92 (td, J = 7.9, 1.7 Hz, 1H), 7.74 (dd, J = 5.8, 2.1 Hz, 1H), 7.57–7.39 (m, 2H), 7.37–7.27 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.14 (s, 1H), 3.80 (s, 3H), 3.39 (d, J = 11.7 Hz, 2H), 2.68 (t, J = 11.5 Hz, 2H), 2.29 (dd, J = 13.7, 8.9 Hz, 5H), 2.14 (s, 3H), 1.85 (d, J = 12.3 Hz, 2H), 1.55 (dd, J = 13.1, 9.4 Hz, 2H).

[0355] Example 14: N 4 -(5-Chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -Preparation of (2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine

[0356]

[0357] Synthesized according to the preparation method of Example 13. MS m / z (ESI): 603.4 [M+H] + 。

[0358] 11H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.92 (td, J = 7.9, 1.7 Hz, 1H), 7.78–7.66 (m, 2H), 7.46 (ddd, J = 7.6, 5.3, 1.9 Hz, 1H), 7.37–7.27 (m, 2H), 6.80 (s, 1H), 6.12 (s, 1H), 3.83 (s, 3H), 2.73–2.62 (m, 2H), 2.37–2.24 (m, 5H), 2.14 (s, 3H), 1.86 (d, J = 12.1 Hz, 2H), 1.65–1.51 (m, 2H).

[0359] Example 15: N 4 -(5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine Preparation

[0360]

[0361] Synthesized by referring to the preparation method of Example 3. MS m / z (ESI): 647.4 [M+H] + 。

[0362] 1 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.63 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.96–7.86 (m, 2H), 7.75 (dd, J = 5.7, 2.1 Hz, 1H), 7.52–7.42 (m, 1H), 7.36–7.28 (m, 2H), 6.83 (s, 1H), 6.12 (s, 1H), 3.83 (s, 3H), 3.28 (t, 2H), 2.94 (t, 2H), 2.71–2.64 (m, 2H), 2.32 (m, 5H), 2.15 (s, 3H), 2.00 (q, J = 7.0 Hz, 2H), 1.86 (d, J = 11.9 Hz, 2H), 1.59 (q, J = 11.0 Hz, 2H).

[0363] Example 16: N 4 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)-N 6Preparation of -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine

[0364]

[0365] Synthesized according to the preparation method of Example 3. MS m / z(ESI): 597.4 [M+H] + 。

[0366] 1 H NMR(400 MHz, DMSO-d6) δ 9.59(s, 1H), 8.43(d, J = 5.6 Hz, 1H), 8.37(s, 1H), 8.25(s, 1H), 7.99(d, J = 2.0 Hz, 1H), 7.91(td, J = 7.9, 1.9 Hz, 1H), 7.73(dd, J = 5.7, 2.1 Hz, 1H), 7.46(tdd, J = 7.5, 5.1, 1.9 Hz, 1H), 7.42–7.27(m, 2H), 7.20(s, 1H), 6.72(s, 1H), 5.90(s, 1H), 3.76(s, 3H), 3.10(d, J = 11.3 Hz, 2H), 2.69–2.59(m, 2H), 2.37(brs, 4H), 2.29(q, J = 7.4 Hz, 2H), 2.16(s, 3H), 1.97–1.78(m, 2H), 1.66–1.48(m, 2H), 0.98(t, J = 7.1 Hz, 3H).

[0367] Example 17: N 4 -(2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine

[0368]

[0369] Synthesized according to the preparation method of Example 13. MS m / z(ESI): 607.4 [M+H] + 。

[0370] 11H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.96 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.92 (td, J = 7.9, 1.9 Hz, 1H), 7.74 (dd, J = 5.7, 2.1 Hz, 1H), 7.69 (s, 1H), 7.47 (tdd, J = 7.3, 5.0, 1.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.23 (s, 1H), 6.07 (s, 1H), 2.71–2.61 (m, 2H), 2.37–2.25 (m, 4H), 2.14 (s, 3H), 1.90–1.82 (m, 2H), 1.57 (dd, J = 11.9, 3.6 Hz, 2H).

[0371] Example 18: N 4 -(2-Chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-Fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine Preparation

[0372]

[0373] Synthesized by referring to the preparation method of Example 13. MS m / z (ESI): 587.4 [M+H] + .

[0374] 1 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.82 (s, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (ddd, J = 7.4, 5.2, 2.1 Hz, 1H), 7.37–7.23 (m, 3H), 7.08 (s, 1H), 5.87 (s, 1H), 3.10 (d, J = 11.3 Hz, 2H), 2.60 (t, J = 11.6 Hz, 2H), 2.30 (tt, J = 11.0, 3.4 Hz, 4H), 2.22 (s, 3H), 2.14 (s, 3H), 1.86 (d, J = 12.0 Hz, 2H), 1.56 (tt, J = 11.8, 5.9 Hz, 2H).

[0375] Biological test evaluation

[0376] (Cell Proliferation Assay)

[0377] (1) Reagents and Consumables

[0378] DMEM medium (Gibco, 11965118)

[0379] RPMI1640 medium (Gibco, 11875119)

[0380] Fetal bovine serum FBS (GBICO, Cat#10099 - 141)

[0381] Luminescent cell viability detection kit (Promega, Cat#G7572)

[0382] Black transparent flat - bottom 96 - well plate Cat#3603

[0383] (2) Instruments

[0384] SpectraMax multi - label microplate reader MD, 2104 - 0010A;

[0385] Carbon dioxide incubator, Thermo Scientific 3100 series;

[0386] Biological safety cabinet, Thermo Scientific, 1300 series A2 type;

[0387] Inverted microscope, Olympus, CKX41SF;

[0388] Siemens refrigerator, KK25E76TI.

[0389] (3) Cell Lines and Culture Conditions

[0390] No. Cell line Cell culture medium Cell density 1 A431 DMEM + 15% FBS 5000 2 Ba / F3 EGFR-L858R-C797S RPMI1640 + 10% FBS 3000 3 Ba / F3 EGFR-Del19-C797S RPMI1640 + 10% FBS 3000 4 Ba / F3 EGFR-L858R RPMI1640 + 10% FBS 3000 5 Ba / F3 EGFR-Del19 RPMI1640 + 10% FBS 3000

[0391] (4) Experimental Procedures

[0392] 1. Cell Culture and Seeding:

[0393] (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%.

[0394] (2) Adjust the cell concentration to reach the desired final density; add 90 μL of cell suspension to the 96 - well plate.

[0395] (3) Incubate the cells in the 96 - well plate overnight at 37°C, 5% CO₂ and 95% humidity.

[0396] 2. T0 Reference Data:

[0397] (1) Add 10 μL of PBS to each well of the T0 plate containing cells.

[0398] (2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0399] (3) Add an equal volume of CTG solution to each well.

[0400] (4) Vortex on an orbital shaker for 5 minutes to lyse the cells.

[0401] (5) Leave the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal.

[0402] (6) Read the T0 fluorescence signal value.

[0403] 3. Compound Dilution and Addition

[0404] (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.

[0405] (2) Prepare compound solutions diluted 1000-fold and 3.16-fold.

[0406] (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 inoculated with cells. Set three replicate wells for each compound concentration, and the final concentration of DMSO is 0.1%.

[0407] (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.

[0408] 4. Fluorescence Signal Reading

[0409] (1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0410] (2) Add an equal volume of CTG solution to each well.

[0411] (3) Vortex on an orbital shaker for 5 minutes to lyse the cells.

[0412] (4) Leave the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal.

[0413] (5) Read the fluorescence value.

[0414] 5. Data Processing

[0415] GraphPad Prism 7.0 software was used to analyze the data, and non-linear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC 50 value (unit: nM) was calculated accordingly. The specific experimental results are shown in Table 1:

[0416] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0417] Table 1: Biological test results

[0418]

[0419]

[0420] From the biological activity data of the specific example compounds, the series of compounds of the present invention have strong inhibitory effects on EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation at the cellular level, and have high selectivity for EGFR WT.

[0421] All documents mentioned in the present invention are cited herein by reference as if each document was individually cited as 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 (III) or a pharmaceutically acceptable salt thereof: Among them, X1 and X2 are each independently N or CH; Y is a key, O, S, N(R 14 ), or C(R 15 R 16 ); R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, morpholine, 3- to 6-membered oxacyclic group, 3- to 6-membered azacyclic group, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy and 3- to 6-membered heterooxacyclic group, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, amino, mono-C 1-4 alkylamino and di-C 1-4 alkylamino; R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, 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 groups; R 5a selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 3-6 cycloalkyl; R 5e selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and C 3-6 cycloalkyl; R 14 selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, -S(O) r R8, -C 0-4 alkyl-O-R9, -C(O)OR9, -C(O)R 10 and -C(O)NR 11 R 12 ; R 15 and R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic groups, or, R 15 and R 16 together with the carbon atom directly connected thereto form a C(O), 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, fluorine, chlorine, bromine, 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 groups and =O; Each R8 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 11 R 12 , and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, 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 11 R 12 ; Each R9 is independently 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, and the above groups are independently 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 11 R 12 ; Each R 10 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 heteroepoxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 11 R 12 , and the above groups are independently 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 heteroepoxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 11 R 12 ; Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, 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, mesyl, isopropylsulfonyl, cyclopropylsulfonyl, tosyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, and the above groups are independently 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, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, Alternatively, R 11 and R 12 together with the nitrogen atom directly connected thereto form a 4- to 8-membered heterocyclic group or a 5- to 8-membered heteroaryl group, and the 4- to 8-membered heterocyclic group or 5- to 8-membered heteroaryl group is 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; and Each r is independently 0, 1 or 2.

2. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteriomethyl and dideuteriomethyl.

3. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, morpholine, 3- to 6-membered oxacyclic group, 3- to 6-membered azacyclic group, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy and cyclobutoxy, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl; R 5a is hydrogen; R 5e Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, tri-deutero-methyl and di-deutero-methyl.

4. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 14 selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, and azetidinyl; R 15 and R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, or, R 15 and R 16 together with the carbon atom to which they are directly attached form a C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, or azetidinyl, which groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, and ═O.

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

6. A method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Comprising the following steps: wherein X is chlorine or bromine, and X1, X2, Y, R1, R2, R 5a and R 5e are as defined in claim 1.

7. A pharmaceutical composition comprising the compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

8. Use of the compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 in the preparation of a drug for treating and / or preventing tumors or metastatic diseases that are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

9. The use according to claim 8, wherein, The tumor is cancer.

10. Use of the compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 in the preparation of a drug for preventing and / or treating tumors and / or metastatic diseases caused by excessive proliferation and disorders of induced cell death.

11. The use according to claim 10, wherein, The tumor is cancer.

12. Use of the compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 in the preparation of a drug for preventing and / or treating lung cancer, pancreatic 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, sarcoma, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma that are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

13. The use according to claim 12, 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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