Pyrimidine-4,6-diamine derivatives, a preparation method therefor, and a pharmaceutical application thereof

Abstract

This invention relates to pyrimidine-4,6-diamine derivatives, their preparation methods, and their pharmaceutical applications. In particular, this invention relates to a pyrimidine-4,6-diamine derivative having the structure of formula (I), its preparation method, pharmaceutical compositions containing it, its use as an EGFR inhibitor, and its use in the preparation of medicaments for treating and / or preventing at least part of cancers, tumors, or metastatic diseases associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, especially in the preparation of medicaments for treating and / or preventing hyperproliferative diseases and diseases inducing cell death disorders. The substituents in formula (I) are the same as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically concerning pyrimidine-4,6-diamine derivatives, their preparation methods, and pharmaceutical applications. Prior Technology

[0002] Lung cancer is the leading cause of death from malignant tumors worldwide, posing a serious threat to human health. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases (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 gene mutations and abnormal expression mechanisms have been confirmed to be associated with the pathogenesis of NSCLC, among which EGFR is the main driver gene. The frequency of EGFR activating mutations in NSCLC patients worldwide is approximately 17% (Hirsch, FR et al. Lung cancer: current therapies and new targeted treatments. Lancet).

[0389] (299-311, 2017), East Asian populations are more susceptible, with a mutation frequency of approximately 50% (Passaro, A., Jänne, PA, 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, while deletion mutations in exon 19 (Del19) and L858R point mutations 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 EGFR Tyrosine Kinase Inhibitors in the Management of NSCLC With Uncommon, Non Exon 20 Insertions, EGFR Mutations. Journal of thoracic oncology: official publication 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. First and second generation EGFR tyrosine kinase inhibitors (TKIs) are mainly targeted at these two activating mutations. Compared with platinum-based chemotherapy, first and second generation EGFR TKIs can significantly prolong progression-free survival (Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet. Oncology).

[13] , 239 - 246, 2012); (Sequist, L.V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung 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. EGFR T790M 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 phase III clinical trial FLAURA, osimertinib showed superior efficacy compared to 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, JC et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England Journal of Medicine).

[0378] (113-125, 2018), which directly propelled osimertinib into the ranks of first-line treatment options.

[0003] Despite the significant efficacy of osimertinib, resistance inevitably develops, leading to disease progression. Several EGFR-dependent (on-target) and off-target resistance mechanisms have been reported in preclinical and clinical studies (Passaro, A., Jänne, PA, Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer). [2], 377-391, 2021). Analysis of the phase III FLAURA study showed that approximately 10-15% of patients with osimertinib as first-line treatment for advanced NSCLC developed EGFR-dependent resistance, with C797S on exon 20 being the most prevalent non-dependent mutation, accounting for up to 7% (Ramalingam, SSet 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 in the ATP-binding domain of EGFR, thus leading to resistance. Furthermore, there is no evidence that patients receiving first-line osimertinib develop an acquired EGFR T790M mutation (Ramalingam, S. Set 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 consisting of Del19 / L858R and C797S may be one of the important mechanisms of resistance to first-line osimertinib treatment (Tumbrink, HL, Heimsoeth, A. & Sos, ML. The next tier of EGFR resistance mutations in lung cancer. Oncogene).

[40] , 1-11, 2021), while a new generation of EGFR TKIs with high activity and selectivity against double mutations composed of Del19 / L858R and C797S may serve as a new generation of treatment for patients who have developed resistance to osimertinib as first-line therapy, thus meeting the clinical needs of these patients. Summary of the Invention

[0004] The purpose of this invention is to provide pyrimidine-4,6-diamine derivatives, their preparation methods, and pharmaceutical applications. The series of compounds of this invention exhibit strong inhibitory activity against EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, and show high selectivity for EGFR wild-type. These compounds can be widely used in the preparation of drugs for the treatment and / or prevention of at least some cancers, tumors, or metastatic diseases associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, particularly for the treatment of hyperproliferative diseases and diseases inducing cell death disorders, thus potentially leading to the development of a new generation of EGFR inhibitors.

[0005] The first aspect of the present invention provides a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof: Where X1 and X2 are each independently N or CR7; Z is either N or CH;

[0006] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, hydroxyl, C1-10 alkoxy, C3-12 cycloalkoxy, 3-12 heterocyclic, C6-10 aryloxy, 5-10 heteroaryloxy, -SF5, -S(O)rR8, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C (=NR11)R10, -N(R11)-C(=NR12)R10, and -C(O)NR11R12, wherein the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 member heterocyclic, 3-12 member heterocyclic, C6-10 aryl, C6-10 aryloxy, 5-10 member heteroaryl, 5-10 member heteroaryl, and -NR11R12;

[0007] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O)rR8, -C0-8 alkyl-O-R9, -C0-8 alkyl-C(O)OR9, - C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10 and -C0-8alkyl-C(O)NR11R12, wherein the above groups are independently and as needed further modified by one or more elements selected from deuterium, halogens, Cyano, Nitro, Azide, C1-10 alkyl, Halo-substituted C1-10 alkyl, Deuterated C1-10 alkyl, C2-10 Alkenyl, C2-10 Alkynyl, C3-12 Cycloalkyl, 3-12 Membered Heterocyclic, C6-10 Aryl, 5-10 Membered Heteroaryl, =O, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O) The substituents of OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted;

[0008] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, and 3-12-membered heterocyclic groups; alternatively, R3 and R4 together with the nitrogen atom directly attached to them form a 4-12-membered heterocyclic group. These groups may be further selected as needed by one or more of deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12-membered heterocyclic groups, C6-10 aryl, and 5-10-membered heteroaryl groups. =O, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 The group is replaced by a substituent of -C0-8alkyl-N(R11)-C(O)R10, and the above group may be further replaced by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR 8. Substituents of -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10;

[0009] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O)rR8, -C0-8 alkyl-O-R9, -C0-8 alkyl-C(O)OR9 -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10, or, when m At 2, two adjacent R5 groups together with their directly attached portions form a C5-10 cycloalkyl, 5-10 member heterocyclic, C6-10 aryl, or 5-10 member heteroaryl group, which may be further substituted independently, as needed, with one or more groups selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 member heterocyclic, C6-10 aryl, 5-10 member heteroaryl, =O, -C0-8 alkyl-SF 5. Substituents of -C0-8alkyl-S(O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10;

[0010] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O)rR8, -C0-8 alkyl-O-R9, -C0-8 alkyl-C(O)OR9, -C0-8 alkyl-C(O)R10, -C0-8 alkyl-O C(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10, wherein the above groups are independently and as needed further substituted with one or more of the following: deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, halogenated C1- 10 alkyl, deuterated C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O)rR8, -C0-8 alkyl-O-R9, -C0-8 alkyl-C(O)OR9, -C0-8 alkyl- The substituents of C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted;

[0011] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0- 8-alkyl-OC(O)R10, -CO-8alkyl-NR11R12, -CO-8alkyl-C(=NR11)R10, -CO-8alkyl-N(R11)-C(=NR12)R10, -CO-8alkyl-C(O)NR11R12 and -CO-8alkyl-N(R11)-C(O)R10, or, two R7s together with the directly attached portion to form a C5-10 cycloalkyl, 5-10 member heterocyclic, C6-10 aryl or 5-10-membered heteroaryl groups, wherein the above groups are independently and as needed further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12-membered heterocyclic, C6-10 aryl, 5-10-membered heteroaryl, =O, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR8, -C0-8alkyl- The substituents of O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted;

[0012] Each R8 is independently selected from hydrogen, deuterium, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, and -NR11R12, and the above groups are independently further substituted as needed by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C6-10 aryl, C6-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryl, and -NR11R12;

[0013] Each R9 is independently selected from hydrogen, deuterium, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12-membered heterocyclic, C6-10 aryl, and 5-10-membered heteroaryl, and the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12-membered heterocyclic, 3-12-membered heterocyclic, C6-10 aryl, C6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl, and -NR11R12;

[0014] Each R10 is selected from hydrogen, deuterium, hydroxyl, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 member heterocyclic, 3-12 member heterocyclic, C6-10 aryl, C6-10 aryloxy, 5-10 member heteroaryl, 5-10 member heteroaryl, and -NR11R12, and the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 member heterocyclic, 3-12 member heterocyclic, C6-10 aryl, C6-10 aryl, 5-10 member heteroaryl, 5-10 member heteroaryl, and -NR11R12;

[0015] Each R11 and R12 is independently selected from hydrogen, deuterium, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, sulfinyl, sulfonylurea, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, etc. p-Toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C1-10 alkylamino, di-C1-10 alkylamino, and C1-10 alkylyl groups, which may be further substituted independently as needed with one or more substituents selected from deuterium, halogen, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 member heterocyclic, 3-12 member heterocyclic, C6-10 aryl, C6-10 aryloxy, 5-10 member heteroaryl, 5-10 member heteroaryl, amino, mono-C1-10 alkylamino, di-C1-10 alkylamino, and C1-10 alkylyl groups.

[0016] Alternatively, R11 and R12 together with the nitrogen atom directly attached to them form a 4-10 member heterocyclic group or a 5-10 member heteroaryl group, which may be further substituted as needed by one or more substituents selected from deuterium, halogen, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 member heterocyclic group, 3-12 member heterocyclic group, C6-10 aryl, C6-10 aryloxy, 5-10 member heteroaryl, 5-10 member heteroaryl, amino, mono-C1-10 alkylamino, di-C1-10 alkylamino, and C1-10 alkylacryl. m is 0, 1, 2, 3, 4, or 5; and Each r is independently 0, 1, or 2.

[0017] As a preferred embodiment, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, X1 and X2 are each independently N or CR7;

[0018] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, hydroxyl, C1-4 alkoxy, C3-6 cycloalkoxy, 3-6-membered heterocyclic, C6-8 aryloxy, 5-8-membered heteroaryloxy, -SF5, -S(O)rR8, -C(O)OR9, -C( O)R10 and -OC(O)R10, wherein the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl and -NR11R12;

[0019] R2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 heterocyclic, C6-8 aryl, 5-8 heteroaryl, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C0-4 alkyl-C (O)R10, -CO-4alkyl-OC(O)R10, -CO-4alkyl-NR11R12, -CO-4alkyl-C(=NR11)R10, -CO-4alkyl-N(R11)-C(=NR12)R10 and -CO-4alkyl-C(O)NR11R12, wherein the above groups are independently and as needed further modified by one or more elements selected from deuterium, halogen, cyano, nitro, azide C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C0-4 The substituents of alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10 are substituted;

[0020] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups. Alternatively, R3 and R4 together with the nitrogen atom directly attached to them form a 4-12 member monocyclic or polycyclic heterocyclic group. These groups may be further selected as needed by one or more of the following: deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 member heterocyclic group, C6-8 aryl, 5-8 member heteroaryl, =O, -C0-4alkyl-SF5, -C0-4alkyl-S(O)rR8, -C0-4alkyl-O-R9, -C0-4alkyl-C(O)OR9, -C0-4 Alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10, and the above groups may be further replaced by one or more substituents selected from deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, 3 The substituents of -6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, =O, -C0-4alkyl-SF5, -C0-4alkyl-S(O)rR8, -C0-4alkyl-O-R9, -C0-4alkyl-C(O)OR9, -C0-4alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10 are substituted;

[0021] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C 0-4alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10, or, when m At 2, two adjacent R5 groups together with their directly attached portions form a C5-8 cycloalkyl, 5-8 member heterocyclic, C6-8 aryl, or 5-8 member heteroaryl group. These groups are independently and as needed further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -C0-4alkyl-SF5, -C0-4alkyl-S(O)rR8, -C0-4alkyl-O-R9, -C0-4alkyl-C(O)OR9, -C0-4alkyl-C(O)R10, -C0-4alkyl-OC(O)R10. The substituents of -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10 are substituted;

[0022] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C0-4 alkyl-C(O)R1 0, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10, wherein the above groups are independently and as needed further selected by one or more of deuterium. Halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9 The substituents of -C0-4alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10 are substituted;

[0023] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C0-4 alkyl-C(O)R10, -C0-4 alkyl -OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10, or, two R7s together with the directly attached portion to form a C5-8 cycloalkyl, 5-8 membered heterocyclic, C6-8 aryl or 5-8 member heteroaryl groups, wherein the above groups are independently and as needed further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9. The substituents of -C0-4alkyl-C(O)OR9, -C0-4alkyl-C(O)R10, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10 are substituted;

[0024] Among them, R8, R9, R10, R11, R12, m and r are as described in compound (I).

[0025] As a preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) is the following compound of formula (II): Where X1 and X2 are each independently N or CR7; Z is either N or CH; Y represents a bond, O, S, N (R14), or C (R15R16);

[0026] R1 is selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, hydroxyl, C1-4 alkoxy, C3-6 cycloalkoxy, 3-6-membered heterocyclic, C6-8 aryloxy, and 5-8-membered heteroaryloxy, which may be further substituted independently as needed by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryl, and -NR11R12;

[0027] R2 is selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10 and -C(O)NR11R12, and the above groups are independently and as needed further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azide The substituents include C1-4 alkyl, halogenated C1-4 alkyl, deuterium-substituted C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10;

[0028] R5a, R5b, R5c, R5d, and R5e are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12, and -N(R11)-C(O)R10;

[0029] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10;

[0030] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10;

[0031] R13a, R13b, R13c, and R13d are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, -C0-4 alkyl-SF5, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, and -C0-4 alkyl-C(O)R1. 0, -C0-4alkyl-OC(O)R10, -C0-4alkyl-NR11R12, -C0-4alkyl-C(=NR11)R10, -C0-4alkyl-N(R11)-C(=NR12)R10, -C0-4alkyl-C(O)NR11R12 and -C0-4alkyl-N(R11)-C(O)R10, or, R13a and R13b, R13c and R13d together with the carbon atom directly attached to them to form C(O), C3-6 cycloalkyl or 3-6 member heterocyclic groups;

[0032] R14 is selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, -C0-4 alkyl-S(O)rR8, -C0-4 alkyl-O-R9, -C0-4 alkyl-C(O)OR9, -C0-4 alkyl-C(O)R10 and -C0-4 alkyl-C(O)NR11R12;

[0033] R15 and R16 are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10. Alternatively, R15 and R16 together with their directly attached carbon atoms form a C(O), C3-6 cycloalkyl, or 3-6 member heterocyclic group, which may be further substituted with one or more of the following groups: deuterium, halogen, cyano, nitro, azide, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic group, C6 The substituents are substituted by -8 aryl, 5-8 heteroaryl, =O, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10;

[0034] Among them, R8, R9, R10, R11, R12 and r are as described in compound (I).

[0035] 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, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 heterocyclic, C6-8 aryl, 5-8 heteroaryl, and -SF5, wherein the above groups are independently and as desired further substituted by one or more of the following groups: deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 cycloalkyl, halogenated C1-4 alkyl, C2-4 cycloalkyl, halogenated C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic, C6-8 aryl, 5-8 heteroaryl, and -SF5. Substituents include alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl, 5-8 membered heteroaryl, =O, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10;

[0036] Among them, R8, R9, R10, R11, R12 and r are as described in compound (I).

[0037] 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, C1-4 alkyl, allyl, vinyl, ethynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, hydroxyl, C1-4 alkoxy, C3-6 cycloalkoxy, and 3-6 member heterocyclic, wherein the above groups are independently and as desired further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, and -NR11R12;

[0038] R5a, R5b, R5c, R5d, and R5e are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups;

[0039] R6 is selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, and deuterated C1-4 alkyl;

[0040] Each R7 is independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, and deuterated C1-4 alkyl;

[0041] R11 and R12 are as described in compound (I).

[0042] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, R13a, R13b, R13c, and R13d are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl, or R13a and R13b, R13c and R13d together with the carbon atom directly attached to them form a C(O), C3-6 cycloalkyl, or 3-6 member heterocyclic group;

[0043] R14 is selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, -S(O)rR8, -C0-4 alkyl-O-R9, -C(O)OR9, -C(O)R10 and -C(O)NR11R12;

[0044] R15 and R16 are each independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups. Alternatively, R15 and R16 together with the carbon atom directly attached to them form a C(O), C3-6 cycloalkyl, or 3-6 member heterocyclic group. These groups may be further selected as needed by one or more groups selected from deuterium, halogen, cyano, nitro, azide, etc. The substituents of C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic, C6-8 aryl, 5-8 member heteroaryl, =O, -SF5, -S(O)rR8, -O-R9, -C(O)OR9, -C(O)R10, -OC(O)R10, -NR11R12, -C(=NR11)R10, -N(R11)-C(=NR12)R10, -C(O)NR11R12 and -N(R11)-C(O)R10 are substituted.

[0045] Among them, R8, R9, R10, R11, R12 and r are as described in compound (I).

[0046] As a preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) is the following compound of formula (III): Where X1 and X2 are each independently N or CH; Y represents a bond, O, S, N (R14), or C (R15R16);

[0047] R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, morpholine, 3-6 member oxoheterocyclic, 3-6 member azaheterocyclic, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and 3-6 member heterocyclic, which may be further substituted independently as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, amino, mono-C1-4 alkylamino, and di-C1-4 alkylamino;

[0048] R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and the above groups may be further substituted independently as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, and 3-6 heterocyclic groups;

[0049] R5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, and C3-6 cycloalkyl;

[0050] R5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, and C3-6 cycloalkyl;

[0051] R14 is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, -S(O)rR8, -C0-4 alkyl-O-R9, -C(O)OR9, -C(O)R10 and -C(O)NR11R12;

[0052] R15 and R16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups. Alternatively, R15 and R16 together with the carbon atom directly attached to them form a C(O), C3-6 cycloalkyl, or 3-6 member heterocyclic group. These groups may be further substituted as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic groups, and =O.

[0053] Among them, R8, R9, R10, R11, R12 and r are as described in compound (I).

[0054] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, each R8 is independently selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, and -NR11R12, wherein the aforementioned groups are independently and as desired further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryl, and -NR11R12;

[0055] Each R9 is independently selected from hydrogen, deuterium, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, and 5-8-membered heteroaryl, and the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryl, and -NR11R12;

[0056] Each R10 is selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, and -NR11R12, and the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, and -NR11R12;

[0057] Each R11 and R12 is independently selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and C1-4 alkylyl, and the above groups may be further modified independently as needed. The substance is substituted by one or more substituents selected from deuterium, halogen, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and C1-4 alkylacryl.

[0058] Alternatively, R11 and R12 together with the nitrogen atom directly attached to them form a 4-8 member heterocyclic group or a 5-8 member heteroaryl group, which may be further substituted as needed by one or more substituents selected from deuterium, halogen, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic group, 3-6 member heterocyclic group, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and C1-4 alkylacryl.

[0059] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrazolyl, imidazolyl, oxazolyl and triazolyl, wherein the above groups are independently and as required further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteryl and dideuteryl.

[0060] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, morpholine, 3-6 member oxacyclic, 3-6 member azacyclic, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy, wherein the above groups are independently and as desired further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl;

[0061] R5a is hydrogen;

[0062] R5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, and dideuterylmethyl.

[0063] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R14 is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl and aziridine;

[0064] R15 and R16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, and piperazine; or, R15 and R16 together with the carbon atom directly attached to them form a C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, or aziridine group, which may be further substituted as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteryl, dideuterylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, and =O.

[0065] As the preferred option, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

[0066] A second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising the following steps: Wherein, X is chlorine or bromine, and X1, X2, Z, R1, R2, R3, R4, R5, R6 and m are as described in compound (I).

[0067] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0068] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of at least part of cancer, tumor or metastatic disease associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0069] This invention also relates to the use of compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of tumors, cancers, and / or metastatic diseases caused by excessive proliferation and induced cell death disorders. This invention further relates to the use of the aforementioned compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous cell carcinoma associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation.

[0070] The present invention also relates to the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and their action as a drug.

[0071] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof for the treatment and / or prevention of cancer, tumors or metastatic diseases at least in part associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

[0072] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

[0073] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, for the treatment and / or prevention of at least part of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with inverted papilloma.

[0074] The present invention also relates to a method for treating and / or preventing cancer, tumor, or metastatic disease at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0075] The present invention also relates to a method for preventing and / or treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induced cell death disorders, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0076] The present invention also relates to a method for treating and / or preventing at least some of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal and sinus inverted papilloma, or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. Implementation

[0077] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a pyrimidine-4,6-diamine derivative having the structure of formula (I). This series of compounds can be widely used in the preparation of drugs for the treatment and / or prevention of at least some cancers, tumors, or metastatic diseases associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, particularly for the treatment of hyperproliferative diseases and diseases inducing cell death disorders, and hold promise for development into a new generation of EGFR inhibitors. Based on this, the present invention was completed.

[0078] Detailed explanation: Unless otherwise stated or specifically stated, the following terms used in the specification and the claims have the following meanings.

[0079] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably including straight-chain alkyl groups with 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and branched alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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 their various branched isomers, etc. "C1-10 alkyl" refers to straight-chain alkyl and branched alkyl with 1 to 10 carbon atoms, "C1-4 alkyl" refers to straight-chain alkyl and branched alkyl with 1 to 4 carbon atoms, "C0-8 alkyl" refers to straight-chain alkyl and branched alkyl with 0 to 8 carbon atoms, and "C0-4 alkyl" refers to straight-chain alkyl and branched alkyl with 0 to 4 carbon atoms.

[0080] The alkyl group may be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O) The substituents of -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0081] "Cycloalkyl" or "carbocyclic" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Cycloalkyl groups are classified as monocyclic or polycyclic, preferably comprising 3 to 12, 3 to 8, or 3 to 6 carbon atoms. For example, "C3-12 cycloalkyl" refers to a cycloalkyl group containing 3 to 12 carbon atoms, "C3-6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, "C5-10 cycloalkyl" refers to a cycloalkyl group containing 5 to 10 carbon atoms, and "C5-8 cycloalkyl" refers to a cycloalkyl group containing 5 to 8 carbon atoms.

[0082] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl.

[0083] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the rings. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups. Spirocycloalkyl groups include, but are not limited to:

[0084] "Fused cyclic alkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring shares a pair of adjacent carbon atoms with the other rings in the system. One or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. Based on the number of constituent rings, fused cyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cyclic alkyl groups include, but are not limited to:

[0085] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0086] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0087] The cycloalkyl group may be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S( The substituents of -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0088] "Heterocyclic group" or "heterocycle" refers to a substituent for a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. One or more (preferably 1, 2, 3, or 4) ring atoms in the heterocyclic group are selected from nitrogen, oxygen, S(O) (=NH), or S(O)r (where r is an integer 0, 1, or 2), but excluding ring portions of -OO-, -OS-, or -SS-. The remaining ring atoms are carbon. Preferably, a heterocyclic group includes 3 to 12, 3 to 8, 3 to 6, or 5 to 6 ring atoms. For example, "3-6 member heterocyclic group" refers to a cyclic group containing 3 to 6 ring atoms. "12-membered heterocyclic group" refers to a cyclic group containing 3 to 12 ring atoms; "4-8-membered heterocyclic group" refers to a cyclic group containing 4 to 8 ring atoms; "4-10-membered heterocyclic group" refers to a cyclic group containing 4 to 10 ring atoms; "4-12-membered heterocyclic group" refers to a cyclic group containing 4 to 12 ring atoms; "5-6-membered heterocyclic group" refers to a cyclic group containing 5 to 6 ring atoms; "5-8-membered heterocyclic group" refers to a cyclic group containing 5 to 8 ring atoms; "5-10-membered heterocyclic group" refers to a cyclic group containing 5 to 10 ring atoms.

[0089] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.

[0090] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O)r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between the rings. Spiroheterocyclic groups include, but are not limited to:

[0091] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more (preferably 1, 2, 3, or 4) rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. One or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O)r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Based on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups. Fused heterocyclic groups include, but are not limited to:

[0092] "Bridged heterocyclic groups" refer to polycyclic heterocyclic groups in which any two rings share two non-directly bonded atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. One or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, S(O) (=NH), or S(O)r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0093] The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0094] The heterocyclic group may be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12-membered heterocyclic, C6-10 aryl, 5-10-membered heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S( The substituents of -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0095] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, preferably an all-carbon aryl group containing 6-10, 6-8, or 6 carbons. For example, "C6-10 aryl" refers to an all-carbon aryl group containing 6-10 carbons, and "C6-8 aryl" refers to an all-carbon aryl group 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, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0096] The "aryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) substituents, independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 Alkyl, deuterium-substituted C1-10 alkyl, C3-12 cycloalkyl, 3-12 member heterocyclic, C6-10 aryl, 5-10 member heteroaryl, =O, -C0-8alkyl-SF5, -C0-8alkyl-S(O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted by substituents.

[0097] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, or 2). Preferably, it contains 5-10, 5-8, or 5-6 ring atoms. For example, "5-8 member heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10 member heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0098] "Heteroaryl" can be substituted or unsubstituted as needed. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 member heterocyclic, C6-10 aryl, 5-10 member heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S The substituents of (O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0099] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight-chain or branched alkenyl group containing 2-10 or 2-4 carbon atoms. For example, "C2-10 alkenyl" refers to a straight-chain or branched alkenyl group containing 2-10 carbon atoms, and "C2-4 alkenyl" refers to a straight-chain or branched alkenyl group containing 2-4 carbon atoms. This includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0100] "Alkenyl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S( The substituents are O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10.

[0101] "Alkynyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched alkynyl group containing 2-10 or 2-4 carbon atoms. For example, "C2-10 alkynyl" refers to a straight-chain or branched alkynyl group containing 2-10 carbon atoms, and "C2-4 alkynyl" refers to a straight-chain or branched alkynyl group containing 2-4 carbon atoms. This includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0102] "Alkynyl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 member heterocyclic, C6-10 aryl, 5-10 member heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S(O) The substituents of -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0103] "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above. For example, "C1-10 alkoxy" refers to alkyloxy groups containing 1-10 carbons, and "C1-4 alkoxy" refers to alkyloxy groups containing 1-4 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0104] "Alkoxy" can be substituted or unsubstituted as needed. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S The substituents of (O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0105] “Cycloalkoxy” refers to -O-cycloalkyl, where cycloalkyl is defined as described above. For example, “C3-12 cycloalkoxy” refers to cycloalkyloxy containing 3-12 carbons, and “C3-8 cycloalkoxy” refers to cycloalkyloxy containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0106] The "cycloalkoxy" group may be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12 heterocyclic, C6-10 aryl, 5-10 heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S The substituents of (O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0107] "Heterocyclic group" refers to -O-heterocyclic group, where the definition of heterocyclic group is as described above. Heterocyclic group oxygen groups include, but are not limited to, azirrocyclobutyroxy, oxocyclobutyroxy, azirrocyclopentyloxy, nitrogen, oxocyclohexyloxy, etc.

[0108] The "heterocyclic group" may be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azide, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, halosubstituted C1-10 alkyl, deuterated C1-10 alkyl, C3-12 cycloalkyl, 3-12-membered heterocyclic, C6-10 aryl, 5-10-membered heteroaryl, =O, -C0-8 alkyl-SF5, -C0-8 alkyl-S The substituents of (O)rR8, -C0-8alkyl-O-R9, -C0-8alkyl-C(O)OR9, -C0-8alkyl-C(O)R10, -C0-8alkyl-OC(O)R10, -C0-8alkyl-NR11R12, -C0-8alkyl-C(=NR11)R10, -C0-8alkyl-N(R11)-C(=NR12)R10, -C0-8alkyl-C(O)NR11R12 and -C0-8alkyl-N(R11)-C(O)R10 are substituted.

[0109] "C1-10 alkyl" refers to the monovalent group remaining after removing the hydroxyl group from a C1-10 alkyl acid, and is usually also represented as "C0-9 alkyl-C(O)-". For example, "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionic acid; and "C3 alkyl-C(O)-" refers to butyryl or isobutyl.

[0110] “C1-4” refers to “C1-4 alkyl”, “C0-4” refers to “C0-4 alkyl”, “C1-8” refers to “C1-8 alkyl”, and “C0-8” refers to “C0-8 alkyl”, as defined above.

[0111] "-C0-8alkyl-S(O)rR8" means that the sulfur atom in -S(O)rR8 is attached to the CO-8 alkyl group, and the definition of CO-8 alkyl group is as described above.

[0112] "-C0-8alkyl-O-R9" means that the oxygen atom in -O-R9 is attached to the CO-8 alkyl group, and the definition of CO-8 alkyl group is as described above.

[0113] "-C0-8alkyl-C(O)OR9" means that the carbonyl group in -C(O)OR9 is attached to the CO-8 alkyl group, as defined above.

[0114] "-C0-8alkyl-C(O)R10" means that the carbonyl group in -C(O)R10 is attached to the CO-8 alkyl group, as defined above.

[0115] "-C0-8alkyl-OC(O)R10" means that the oxygen atom in -OC(O)R10 is attached to the CO-8 alkyl group, as defined above.

[0116] "-C0-8alkyl-NR11R12" means that the nitrogen atom in -NR11R12 is attached to the CO-8 alkyl group, as defined above.

[0117] "-C0-8alkyl-C(=NR11)R10" means that the carbon atom in -C(=NR11)R10 is attached to the CO-8 alkyl group, as defined above.

[0118] "-C0-8alkyl-N(R11)-C(=NR12)R10" means that the nitrogen atom in -N(R11)-C(=NR12)R10 is attached to the CO-8 alkyl group, as defined above.

[0119] "-C0-8alkyl-C(O)NR11R12" means that the carbonyl group in -C(O)NR11R12 is attached to the CO-8 alkyl group, as defined above.

[0120] "-C0-8alkyl-N(R11)-C(O)R10" means that the nitrogen atom in -N(R11)-C(O)R10 is attached to the CO-8 alkyl group, as defined above.

[0121] "Halogenated C1-10 alkyl" refers to 1-10 carbon alkyl groups on an alkyl group that are replaced by fluorine, chlorine, bromine, or iodine atoms as needed, including but not limited to difluoromethyl (-CHF2), dichloromethyl (-CHCl2), dibromomethyl (-CHBr2), trifluoromethyl (-CF3), trichloromethyl (-CCl3), tribromomethyl (-CBr3), etc.

[0122] "Halogenated C1-10 alkoxy groups" refer to alkoxy groups on alkyl groups where the hydrogen atom on the alkyl group is replaced by fluorine, chlorine, bromine, or iodine atoms as needed. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, and tribromomethoxy.

[0123] "Deuterated C1-10 alkyl" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atoms are replaced by deuterium atoms as needed. This includes, but is not limited to, monodeutermethyl (-CH2D), dideutermethyl (-CHD2), trideutermethyl (-CD3), etc.

[0124] "Deuterated C1-10 alkoxy groups" refers to 1-10 carbon alkyl groups on an alkyl group in which the hydrogen atom is replaced by a deuterium atom as needed. This includes, but is not limited to, monodeuteroxy, dideuteroxy, trideuteroxy, etc.

[0125] "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.

[0126] "As needed" or "as needed" means that the event or circumstance described below may but does not have to occur. This description includes the possibility or absence of the event or circumstance, that is, it includes both substituted and unsubstituted cases. For example, "heterocyclic groups substituted with alkyl groups as needed" means that alkyl groups may but do not have to be present. This description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

[0127] "Substituted" refers to one or more hydrogen atoms in a group being independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, conforming to the valence bond theory in chemistry, and that someone with ordinary knowledge in the relevant technical field can determine (by experiment or theory) whether the substitution is possible or impossible without much effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0128] Stereoisomers, also known as cis-trans isomers, are isomers formed by different spatial arrangements of atoms in a molecule. They can be classified into two main categories: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers resulting from bond length, bond angle, the presence of double bonds, or rings within the molecule are called configuration stereo-isomers. Configuration stereo-isomers are further divided into two categories. Isomers resulting from the inability of single bonds in double bonds or cyclic carbon atoms to rotate freely are called geometric isomers, also known as cis-trans isomers, and have two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. If the compounds of this invention contain double bonds, unless otherwise specified, it can be understood as containing E and / or Z-type isomers. Stereoisomers with different optical rotation properties due to the lack of antiaxial symmetry in the molecule are called optical isomers, and are classified into R and S configurations. In this invention, unless otherwise specified, "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configuration isomers, and conformational isomers, preferably the S configuration.

[0129] In this invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt or base addition salt, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0130] "Pharmaceutical composition" refers to a mixture containing one or more of the compound described herein or its physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate drug delivery to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0131] [The present invention will be further described in detail and completely below with reference to embodiments, but this is in no way a limitation of the present invention, nor is the present invention limited to the content of the embodiments.]

[0132] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer with deuterated dimethyl monoxide (DMSO-d6), deuterated methanol (MeOH-d4), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0133] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. High-performance liquid chromatography (HPLC) was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0134] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm~0.20mm, while the standard size for TLC separation and purification is 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai 200~300 mesh silica gel as the carrier.

[0135] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0136] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0137] [I. Preparation of Intermediates]

[0138] [Preparation of Intermediate 1: 2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0139] [Step 1: Synthesis of 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0140] 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) and stirred overnight at 80 °C under nitrogen protection. The reaction 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 and concentration, column chromatography was used 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]+.

[0141] [Step 2: Synthesis of 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0142] 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, and then stirred at room temperature for 1 hour under a hydrogen atmosphere 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]+.

[0143] [Preparation of intermediate 2: 2-methoxy-5-methyl-4-(4-N-morpholinylpiperidin-1-yl)aniline]

[0144] [Step 1: Synthesis of 2-methoxy-5-methyl-4-(4-N-morpholinylpiperidin-1-yl)aniline]

[0145] 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.73 g, 3.94 mmol) was added to DMSO (20 mL), followed by K₂CO₃ (1.09 g, 7.89 mmol) and 4-(piperidin-4-yl)morpholine (0.81 g, 4.73 mmol). The reaction was carried out overnight at 80 °C, followed by a further reaction at 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. The mixture was filtered, concentrated, and separated by column chromatography [evolving solvent: CH₂Cl₂ / MeOH (+1% ammonia) = 0–10%] to give 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]⁺.

[0146] [Step 2: Synthesis of 2-methoxy-5-methyl-4-(4-N-morpholinylpiperidin-1-yl)aniline]

[0147] 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 Pd / C (0.10 g, 10%) was added. After purging with hydrogen three times, the reaction was carried out overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through diatomaceous earth, and the crude product obtained after concentration was separated by column chromatography [developing solvent: CH2Cl2 / MeOH (+1% ammonia) = 0~10%] to give 2-methoxy-5-methyl-4-(4-N-morpholinylpiperidin-1-yl)aniline (0.81 g, yield: 80.2%). MS m / z (ESI): 306.2 [M+H]+.

[0148] [Preparation of intermediate 3: 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0149] [Step 1: Synthesis of 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene]

[0150] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), followed by the addition of K₂CO₃ (969.16 mg, 7.01 mmol) and iodoethane (0.37 mL, 4.68 mmol), and the mixture was stirred overnight. After the reaction was complete, 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]+.

[0151] [Step 2: Synthesis of 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0152] 1-Ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, 2.11 mmol) was dissolved in DMSO (10 mL), followed by the addition of K₂CO₃ (582 mg, 4.22 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (580 mg, 3.16 mmol). The mixture was stirred overnight at 90 °C. After the reaction was complete, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to give 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]+.

[0153] [Step 3: Synthesis of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0154] 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 complete, 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]+.

[0155] [Preparation of intermediate 4: 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0156] [Step 1: Synthesis of 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene]

[0157] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), and Na₂CO₃ (743 mg, 7.01 mmol) was added. The reaction mixture 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 complete, the 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. The mixture was filtered, and the filtrate was concentrated to give 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, yield: 92.9%). MS m / z (ESI): 222.0 [M+H]⁺.

[0158] [Step 2: Synthesis of 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0159] 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, 2.17 mmol) was dissolved in DMSO (10 mL), followed by the addition of K₂CO₃ (750 mg, 5.43 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (597 mg, 3.26 mmol). The mixture was stirred overnight at 90 °C. After the reaction was complete, the solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give 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]+.

[0160] [Step 3: Synthesis of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0161] 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 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and separated by column chromatography to give 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]+.

[0162] [Preparation of intermediate 5: 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline]

[0163] [Step 1: Synthesis of 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene]

[0164] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (15 mL), followed by the addition of K₂CO₃ (969 mg, 7.01 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.67 mL, 4.68 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give 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]+.

[0165] [Step 2: Synthesis of 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine]

[0166] 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 complete, the solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give 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]+.

[0167] [Step 3: Synthesis of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline]

[0168] 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, and the mixture was stirred at 85 °C for 2 hours. After the reaction was complete, 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]+.

[0169] [Preparation of intermediate 6: 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0170] [Step 1: Synthesis of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0171] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.40 g, 5.60 mmol) was dissolved in dimethylamine (10.0 mL), followed by the addition of K₂CO₃ (1.55 g, 11.20 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.54 g, 8.40 mmol). The reaction mixture was heated to 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was extracted with dichloromethane and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. 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]+.

[0172] [Step 2: Synthesis of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine]

[0173] 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), followed by the addition of potassium vinyltrifluoroborate (259 mg, 1.94 mmol), Na₂CO₃ (308 mg, 2.90 mmol), and Pd(dppf)Cl₂ (70.8 mg, 0.10 mmol). The mixture was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, yield: 86.0%). MS m / z (ESI): 361.0 [M+H]⁺.

[0174] [Step 3: Synthesis of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0175] 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, 0.83 mmol) was dissolved in methanol (20 mL), and then Pd / C (30 mg, 10%) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere at atmospheric pressure. After the reaction was complete, the mixture was filtered, and the crude product was concentrated and separated 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]+.

[0176] [Preparation of intermediate 7: 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0177] [Step 1: Synthesis of 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidin-4-yl)-4-methylpiperazine]

[0178] 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) was placed in 1,4-dioxane (10 mL) and water (3 mL), followed by the addition of 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-dioxaborhecyclopentane (0.20 mL, 1.04 mmol). The mixture was heated to 90 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was then washed with saturated brine and dried over sodium sulfate. After filtration and concentration, the crude product was separated 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]+.

[0179] [Step 2: Synthesis of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0180] 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 under a hydrogen atmosphere at atmospheric pressure for 3 hours. The reaction solution was filtered through diatomaceous earth, and the crude product obtained after concentration was separated by column chromatography [evolving solvent: CH2Cl2 / MeOH (+1% ammonia) = 0~10%) to give 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]+.

[0181] [Preparation of intermediate 8: 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0182] [Step 1: Synthesis of 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0183] In a toluene (10 mL) solution of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol), 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, and the mixture was heated to 120 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The sample was filtered, 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]+.

[0184] [Step 2: Synthesis of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0185] 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), and Fe powder (0.18 g, 3.23 mmol) and NH4Cl (0.35 g, 6.47 mmol) were added. The mixture was heated to 70 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the crude product obtained after concentration 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]+.

[0186] [Preparation of Intermediate 9: 2-Methoxy-5-(1-Methyl-1H-pyrazol-4-yl)-4-N-morpholinoaniline]

[0187] [Step 1: Synthesis of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole]

[0188] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (900 mg, 3.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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) and heated to 100 °C with stirring overnight under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to obtain 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (900 mg, yield: 99.5%). MS m / z (ESI): 252.1 [M+H]+.

[0189] [Step 2: Synthesis of 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)morpholine]

[0190] 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 10 mL of DMSO and heated to 100 °C with stirring overnight under nitrogen protection. 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 give 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)morpholine (160 mg, yield: 84.2%). MS m / z (ESI): 319.1 [M+H]+.

[0191] [Step 3: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-N-morpholinoaniline]

[0192] 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)morpholine (160 mg, 0.52 mmol) was placed in methanol (10 mL), followed by the addition of 10% Pd / C (20 mg). The mixture was stirred at room temperature for 30 minutes under a normal hydrogen atmosphere. The reaction solution was filtered, and the crude product was concentrated and separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-N-morpholinoaniline (106 mg, yield: 68.3%). MS m / z (ESI): 289.1 [M+H]+.

[0193] [Preparation of Intermediate 10: 2-Methoxy-5-(1-Methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline]

[0194] [Step 1: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-methylpiperazine]

[0195] 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 heated to 100 °C with stirring overnight under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with resaturated 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-pyrazole-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, yield: 75.8%). MS m / z (ESI): 332.1 [M+H]+.

[0196] [Step 2: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylpiperazin-1-yl)aniline]

[0197] 1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, 0.45 mmol) was placed in methanol (10 mL), and then 10% Pd / C (20 mg) was added. The mixture was stirred at room temperature for 30 minutes under a normal hydrogen atmosphere. The reaction solution was filtered, and the crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazin-1-yl)aniline (68 mg, yield: 50.3%). MS m / z (ESI): 302.1 [M+H]+.

[0198] [Preparation of Intermediate 11: 2-Methoxy-5-(1-Methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0199] [Step 1: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0200] 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.30 g, 1.19 mmol) was dissolved in dimethylamine (5 mL), followed by the addition of K₂CO₃ (0.50 g, 3.58 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (0.88 g, 4.78 mmol). The reaction mixture was heated to 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. The mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.23 g, yield: 44.7%). MS m / z(ESI):415.2[M+H]+.

[0201] [Step 2: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0202] 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), and 10% Pd / C (0.10 g) was added. The atmosphere was purged with hydrogen, and the reaction was carried out overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through diatomaceous earth, 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]+.

[0203] [Preparation of Intermediate 12: 5-Fluoro-2-methoxy-4-[4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl]aniline]

[0204] [Step 1: Synthesis of 4,5-difluoro-2-methoxy-1-nitrobenzene]

[0205] Under ice-water 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, followed by slow dropwise addition of concentrated HNO₃ (1.37 g, 15.27 mmol). After the addition was complete, the reaction mixture was allowed to react 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 NaHCO₃ aqueous solution and saturated NaCl solution. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give compound 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol, 43.3%).

[0206] [Step 2: Synthesis of 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine]

[0207] To a solution of 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol) in 1,4-dioxane (10 mL), 1-methyl-4-(piperidin-4-yl)piperazine (1.10 g, 6.00 mmol) and DIPEA (1.94 g, 14.99 mmol) were added, and the mixture was heated to 100 °C and stirred for 2 hours under N2 protection. After the reaction was complete, it was cooled to room temperature. The reaction solution was concentrated to obtain crude 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridin-4-yl]-4-methylpiperazine, which was used directly in the next reaction.

[0208] [Step 3: Synthesis of 5-fluoro-2-methoxy-4-[4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl]aniline]

[0209] The crude 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridin-4-yl]-4-methylpiperazine (2.26 g, 5.99 mmol) was mixed with 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). The mixture was heated to 75 °C and stirred for 3 hours under N2 protection. After the reaction was complete, the mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was extracted with ammonia and then with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give 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]+.

[0210] [Preparation of Intermediate 13: 5-Chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0211] The intermediate 12 was synthesized from 1-chloro-2-fluoro-4-methoxybenzene according to the preparation method. MS m / z (ESI): 339.2 [M+H]+.

[0212] [Preparation of intermediate 14: 2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0213] The intermediate 12 was synthesized from 1,4-dichloro-2-fluorobenzene according to the preparation method. MS m / z (ESI): 343.2 [M+H]+.

[0214] [Preparation of Intermediate 15: 2-Chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline]

[0215] The intermediate was synthesized from 1-chloro-5-fluoro-4-methyl-2-nitrobenzene according to the preparation method of intermediate 1. MS m / z (ESI): 323.2 [M+H]+.

[0216] [Preparation of Intermediate 16: 2-Methoxy-5-methyl-4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)aniline]

[0217] The synthesis was performed following the preparation method of intermediate 1. MS m / z (ESI): 333.2 [M+H]+.

[0218] [II. Preparation of Specific Embodiments]

[0219] [Example 1: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Preparation of [-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0220] [Step 1: Synthesis of 2-(2-fluorophenyl)pyridine-4-amine]

[0221] 2-Bromopyridine-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), followed by the addition of Na₂CO₃ aqueous solution (2 M, 86.7 mL, 173.40 mmol) and Pd(PPh₃)₄ (1.34 g, 1.16 mmol). The reaction mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, and saturated brine (600 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was separated by column chromatography [extractant: EtOAc / PE = 0–50%] to give 2-(2-fluorophenyl)pyridine-4-amine (10.0 g, yield: 92%). MS m / z (ESI): 189.0 [M+H]⁺.

[0222] [Step 2: Synthesis of 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine]

[0223] 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 ice-water bath cooling. The mixture was stirred at room temperature for 1 hour, and then 4,6-dichloropyrimidine (4.75 g, 31.88 mmol) was added under ice-water bath cooling. The mixture was then 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)pyrimidine-4-amine (1 g, yield: 12.5%). MS m / z (ESI): 301.2 [M+H]+.

[0224] [Step 3: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Synthesis of [-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0225] 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), followed by the addition of 4M HCl / dioxane solution (0.17 mL, 0.67 mmol). The mixture was stirred overnight at 120 °C. The reaction solution was neutralized with NH3 / MeOH solution, concentrated, and separated by reversed-phase column chromatography to obtain N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-4,6-diamine (21.5 mg, yield: 22.9%). MS m / z(ESI):583.2[M+H]+.

[0226] ¹H NMR (400MHz, Methanol-d⁴)δ 8.27(d,J=5.9Hz,1H),8.17(s,1H),7.82(s,1H),7.64-6.59(m,2H),7.39-7.3 3(m,1H),7.20(t,J=7.5Hz,1H),7.15-7.09(m,2H),6.66(s,1H),5.95(s,1H),3 .72(s,3H),3.08(d,J=11.9Hz,2H),2.65-2.53(m,6H),2.48-2.41(m,4H),2.3 1-2.5(m,1H),2.22(s,3H),2.14(s,3H),1.94-1.88(m,2H),1.65-1.56(m,2H).

[0227] [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]

[0228] 2-Methoxy-5-methyl-4-(4-N-morpholinylpiperidin-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 10 mL of tributanol, followed by the addition of p-toluenesulfonic acid monohydrate (0.60 g, 3.18 mmol). The mixture was heated to 100 °C and reacted for 36 hours. The reaction solution was cooled to room temperature, neutralized with ammonia water, and the crude product was concentrated and separated by column chromatography to obtain N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(2-methoxy-5-methyl-4-(4-N-morpholinylpiperidin-1-yl)phenyl)pyrimidin-4,6-diamine (80 mg, yield: 41.1%). MS m / z(ESI): 570.2[M+H]+.

[0229] 1HNMR(400MHz,DMSO-d 6)δ 9.59(s,1H),8.43(d,J=5.6Hz,1H),8.37(s,1H),8.25(s,1H),7.98(d,J=2.0Hz,1H),7.91(td,J=7.9,1.9 Hz,1H),7.73(dd,J=5.7,2.2Hz,1H),7.52-7.41(m,1H),7.36-7.26(m,2H),7.21(s,1H),6.72(s,1H),5.9 0(s,1H),3.76(s,3H),3.59(t,J=4.6Hz,4H),3.11(d,J=11.5Hz,2H),2.92(s,2H),2.64(t,J=11.5Hz,2H) ,2.35-2.21(m,2H),2.17(s,3H),1.99(dt,J=13.2,7.0Hz,1H),1.89(d,J=11.6Hz,2H),1.64-1.49(m,2H).

[0230] [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]

[0231] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (180 mg, 0.60 mmol), 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) and heated to 90 °C with stirring overnight under nitrogen protection. 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 preparative column chromatography to obtain N4-(2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N6-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (65 mg, yield: 18.0%). MS m / z (ESI): 597.3 [M+H]+.

[0232] 1H NMR (400MHz, DMSO-d 6 )δ 9.58(s,1H),8.43(d,J=5.7Hz,1H),8.28(d,J=15.0Hz,2H),7.99(s,1H),7.91(td,J=7.9,1.8Hz,1H), 7.73(dd,J=5.7,2.1Hz,1H),7.49-7.44(m,1H),7.37-7.26(m,2H),7.17(s,1H),6.70(s,1H),5.91(s,1 H),4.02(q,J=7.0Hz,2H),3.43-3.38(m,2H),3.09(d,J=11.4Hz,2H),2.61(t,J=11.5Hz,4H),2.39-2. 26(m,5H),2.16(s,3H),2.15(s,3H),1.85(d,J=11.8Hz,2H),1.62-1.51(m,2H),1.24(t,J=6.9Hz,3H).

[0233] [Example 4: N] [4] [-(2-(difluoromethoxy)-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]

[0234] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (200 mg, 0.67 mmol), 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) and stirred overnight at 90 °C under nitrogen protection. 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 N4-(2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N6-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (25 mg, yield: 6.1%) was then separated using a preparative column. MS m / z (ESI): 619.3 [M+H]+.

[0235] 1H NMR (400MHz, DMSO-d 6 )δ 9.64(s,1H),8.65(s,1H),8.44(d,J=5.7Hz,1H),8.27(s,1H),8.00(s,1H),7.91(td,J=7.9,1.9 Hz,1H),7.73(dd,J=5.7,2.1Hz,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=3.2Hz,1.25H),5.98(s,1H),3.11(d,J=11.4Hz,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=11.0Hz,2H),1.64-1.52(m,2H).

[0236] [Example 5: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Preparation of [-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrimidine-4,6-diamine]

[0237] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (53 mg, 0.18 mmol), 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) and stirred overnight at 90 °C under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. Further separation by preparative column chromatography yielded N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(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]+.

[0238] 1H NMR (400MHz, DMSO-d 6 )δ 9.58(s,1H),8.43(t,J=2.8Hz,2H),8.25(s,1H),7.99(d,J=2.0Hz,1H),7.91(td,J=7.9,2.0Hz,1H),7. 73(dd,J=5.7,2.1Hz,1H),7.46(td,J=5.6,2.6Hz,1H),7.31(dd,J=9.3,6.9Hz,2H),7.16(s,1H),6.84(s ,1H),5.88(s,1H),4.68(q,J=8.9Hz,2H),3.11(d,J=11.5Hz,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=12.1Hz,2H),1.64-1.53​​(m,2H).

[0239] [Example 6: N] [4] [-(5-ethyl-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]

[0240] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.33 mmol), 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) and stirred overnight at 90 °C under nitrogen protection. 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 then separated by preparative column chromatography to obtain N4-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N6-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (38 mg, yield: 19.2%). MS m / z (ESI): 597.3 [M+H]+.

[0241] 1H NMR (400MHz, DMSO-d 6 )δ 9.59(s,1H),8.47-8.36(m,2H),8.26(s,1H),7.98(t,J=1.9Hz,1H),7.91(td,J=7.9,1.9Hz,1H),7. 73(dd,J=5.6,2.1Hz,1H),7.51-7.41(m,1H),7.37-7.27(m,2H),7.23(s,1H),6.78(s,1H),5.90(s,1 H),3.76(s,3H),3.29-3.23(m,2H),3.03(d,J=11.3Hz,2H),2.71-2.64(m,2H),2.57(q,J=7.5Hz,4H ),2.38-2.25(m,5H),2.15(s,3H),1.85(d,J=11.7Hz,2H),1.61-1.51(m,2H),1.16(t,J=7.5Hz,3H).

[0242] [Example 7: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Preparation of [-(5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0243] 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 mixed with 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 mixture was heated to 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The crude product was then separated by preparative column chromatography to obtain N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(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]+.

[0244] 1HNMR(400MHz,DMSO-d 6)δ 9.60(s,1H),8.43(d,J=4.6Hz,2H),8.26(s,1H),7.98(s,1H),7.91(t,J=7.9Hz,1H),7 .73(d,J=4.4Hz,1H),7.46(q,J=6.9Hz,1H),7.31(t,J=7.9Hz,2H),7.26(s,1H),6.81( s,1H),5.88(s,1H),3.76(s,3H),2.98(d,J=11.1Hz,2H),2.71(t,J=11.6Hz,2H),2.32 (s,5H),2.15(s,3H),1.85(d,J=11.9Hz,2H),1.64-1.50(m,2H),1.14(d,J=6.8Hz,6H).

[0245] [Example 8: N] [4] [-(5-Cyclopropyl-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]

[0246] In a 10 mL solution of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.20 g, 0.55 mmol), 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, and the mixture was heated to 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The crude product was then separated by preparative column chromatography to obtain N4-(5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N6-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (96.8 mg, yield: 28.8%). MS m / z (ESI): 609.4 [M+H]+.

[0247] 1HNMR(400MHz,DMSO-d 6)δ 9.58(s,1H),8.42(d,J=5.7Hz,1H),8.34(s,1H),8.24(d,J=0.9Hz,1H),7.98(t,J=1.9Hz,1H),7.91( td,J=7.9,1.9Hz,1H),7.73(dd,J=5.7,2.1Hz,1H),7.46(tdd,J=7.7,5.1,1.9Hz,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=11.2Hz,2H),2.41-2.23(m,5H), 2.19-2.07(m,4H),1.87(d,J=11.7Hz,2H),1.67-1.54(m,2H),0.97-0.87(m,2H),0.63-0.54(m,2H).

[0248] [Example 9: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Preparation of [-(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0249] In a 10 mL toluene 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), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-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, and the mixture was heated to 80 °C overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography. The crude product was then separated by preparative column chromatography to obtain N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(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]+.

[0250] 1HNMR(400MHz,DMSO-d 6)δ 9.60(s,1H),8.45-8.39(m,2H),8.26(d,J=0.8Hz,1H),8.06(s,1H),7.99(t,J=1.9Hz,1H),7.91( td,J=8.0,1.9Hz,1H),7.87(s,1H),7.73(dd,J=5.7,2.1Hz,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=11.1Hz,2H),2.63-2.53(m,4 H),2.39-2.27(m,4H),2.26-2.19(m,1H),2.15(s,3H),1.82(d,J=11.5Hz,2H),1.61-1.48(m,2H).

[0251] [Example 10: N] [4] [-(2-(2-fluorophenyl)pyridin-4-yl)-N] [6] Preparation of [-(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-N-morpholinylphenyl)pyrimidine-4,6-diamine]

[0252] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.33 mmol), 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-N-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) and heated to 90 °C with stirring overnight under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. Further separation by preparative column chromatography yielded N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-N-morpholinylphenyl)pyrimidine-4,6-diamine (40.5 mg, yield: 22.0%). MS m / z (ESI): 553.2 [M+H]+.

[0253] 1H NMR(400MHz, DMSO-d 6)δ 9.62(s,1H),8.46(s,1H),8.43(d,J=5.6Hz,1H),8.27(s,1H),8.13(s,1H),8.00(t,J=2.0Hz, 1H),7.94-7.88(m,2H),7.75-7.73(dd,J=5.7,2.1Hz,1H),7.49-7.44(m,2H),7.34-7.28(m,2 H),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).

[0254] [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]

[0255] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (62 mg, 0.21 mmol), 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) and heated to 90 °C with stirring overnight under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. Further separation by preparative column chromatography yielded N4-(2-(2-fluorophenyl)pyridin-4-yl)-N6-(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]+.

[0256] 1H NMR(400MHz,DMSO-d 6)δ 9.61(s,1H),8.47-8.40(m,2H),8.27(s,1H),8.06(s,1H),7.99(t,J=2.0Hz,1H),7.94-7.87(m,2H),7.74-7.72(dd,J=5.7,2.2Hz,1H),7.5 0-7.42(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).

[0257] [Example 12: N] [4] [-(5-(2-fluorophenyl)pyridin-3-yl)-N] [6] Preparation of [-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0258] [Step 1: Synthesis of 5-(2-fluorophenyl)pyridine-3-amine]

[0259] Refer to the embodiment [1] First step.

[0260] [Step 2: N] [4] [-(5-(2-fluorophenyl)pyridin-3-yl)-N] [6] Synthesis of [-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine]

[0261] 4,6-Dichloropyrimidine (60 mg, 0.40 mmol), 5-(2-fluorophenyl)pyridine-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) were dissolved in anhydrous 1,4-dioxane (8 mL). BrettPhos Pd-G3 (37 mg, 0.04 mmol) and NaO t Bu (77 mg, 0.81 mmol) were added under nitrogen protection, and the mixture was heated to 85 °C and reacted overnight. The reaction solution was cooled to room temperature, concentrated, and then separated by column chromatography. The crude product was further separated by high performance liquid chromatography to obtain N4-(5-(2-fluorophenyl)pyridin-3-yl)-N6-(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]+.

[0262] 1H NMR(400MHz,DMSO-d 6)δ 9.32(s,1H),8.74(d,J=2.1Hz,1H),8.30-8.26(m,2H),8.24(s,1H),8.18(s,1H),7. 57(td,J=7.8,1.8Hz,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=11.3Hz,2H),2.63(t,J=11.4Hz,3H),2.3 7-2.25(m,5H),2.16(s,3H),2.15(s,3H),1.86(d,J=11.9Hz,2H),1.67-1.47(m,2H).

[0263] [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]

[0264] 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)hexahydropyridin-1-yl]aniline (100 mg, 0.307 mmol) were dissolved in 2-butanol (2.0 mL), and TFA (0.4 mL, 5.385 mmol) was added. The mixture was heated to 130 °C overnight under N2 protection in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography to obtain compound N4-(5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N6-(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]+.

[0265] 1H NMR(400MHz,DMSO-d 6)δ 9.68(s,1H),8.55(s,1H),8.45(d,J=5.7Hz,1H),8.31(d,J=0.9Hz,1H),8.00(d,J=2.0Hz,1H),7 .92(td,J=7.9,1.7Hz,1H),7.74(dd,J=5.8,2.1Hz,1H),7.57-7.39(m,2H),7.37-7.27(m,2H),6 .68(d,J=8.3Hz,1H),6.14(s,1H),3.80(s,3H),3.39(d,J=11.7Hz,2H),2.68(t,J=11.5Hz,2H), 2.29(dd,J=13.7,8.9Hz,5H),2.14(s,3H),1.85(d,J=12.3Hz,2H),1.55(dd,J=13.1,9.4Hz,2H).

[0266] [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]

[0267] Synthesized according to the preparation method of Example 13. MS m / z (ESI): 603.4 [M+H]+.

[0268] 1H NMR(400MHz,DMSO-d 6)δ 9.69(s,1H),8.59(s,1H),8.45(d,J=5.7Hz,1H),8.32(d,J=0.9Hz,1H),8.00(d,J= 1.9Hz,1H),7.92(td,J=7.9,1.7Hz,1H),7.78-7.66(m,2H),7.46(ddd,J=7.6,5.3, 1.9Hz,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=12.1Hz,2H),1.65-1.51(m,2H).

[0269] [Example 15: N] [4] [-(5-bromo-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]

[0270] Synthesized according to the preparation method in Example 3. MS m / z (ESI): 647.4 [M+H]+.

[0271] 1H NMR(400MHz,DMSO-d 6)δ 9.72(s,1H),8.63(s,1H),8.45(d,J=5.8Hz,1H),8.32(s,1H),8.00(s,1H),7.96-7.8 6(m,2H),7.75(dd,J=5.7,2.1Hz,1H),7.52-7.42(m,1H),7.36-7.28(m,2H),6.83(s,1 H),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=7.0Hz,2H),1.86(d,J=11.9Hz,2H),1.59(q,J=11.0Hz,2H).

[0272] [Example 16: N] [4] [-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)-N] [6] Preparation of [-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine]

[0273] Synthesized according to the preparation method in Example 3. MS m / z (ESI): 597.4 [M+H]+.

[0274] 1H NMR(400MHz,DMSO)δ 9.59(s,1H),8.43(d,J=5.6Hz,1H),8.37(s,1H),8.25(s,1H),7.99(d,J=2.0Hz,1H),7.91(td,J=7.9,1.9Hz,1H),7.7 3(dd,J=5.7,2.1Hz,1H),7.46(tdd,J=7.5,5.1,1.9Hz,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=11.3Hz,2H),2.69-2.59(m,2H),2.37(brs,4H),2.29(q,J=7 .4Hz,2H),2.16(s,3H),1.97-1.78(m,2H),1.66-1.48(m,2H),0.98(t,J=7.1Hz,3H).

[0275] [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]

[0276] Synthesized according to the preparation method of Example 13. MS m / z (ESI): 607.4 [M+H]+.

[0277] 1H NMR(400MHz,DMSO-d 6)δ 9.75(s,1H),8.96(s,1H),8.46(d,J=5.7Hz,1H),8.32(s,1H),8.02(s,1H),7.92(t d,J=7.9,1.9Hz,1H),7.74(dd,J=5.7,2.1Hz,1H),7.69(s,1H),7.47(tdd,J=7.3,5 .0,1.9Hz,1H),7.31(d,J=7.9Hz,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=11.9,3.6Hz,2H).

[0278] [Example 18: N] [4] [-(2-chloro-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]

[0279] Synthesized according to the preparation method of Example 13. MS m / z (ESI): 587.4 [M+H]+.

[0280] 1H NMR(400MHz,DMSO-d 6)δ 9.67(s,1H),8.82(s,1H),8.44(d,J=5.8Hz,1H),8.28(s,1H),8.00(d,J=1.8Hz,1H),7.91(td, J=7.9,1.9Hz,1H),7.73(dd,J=5.7,2.1Hz,1H),7.46(ddd,J=7.4,5.2,2.1Hz,1H),7.37-7.23(m ,3H),7.08(s,1H),5.87(s,1H),3.10(d,J=11.3Hz,2H),2.60(t,J=11.6Hz,2H),2.30(tt,J=11 .0,3.4Hz,4H),2.22(s,3H),2.14(s,3H),1.86(d,J=12.0Hz,2H),1.56(tt,J=11.8,5.9Hz,2H).

[0281] [Biology Test Evaluation]

[0282] [(Cell proliferation experiment)]

[0283] (a) Reagents and Consumables DMEM medium (Gibco, 11965118) RPMI 1640 medium (Gibco, 11875119) Fetal bovine serum FBS (GBICO, Cat#10099-141) CellTiter-Glo® Chemiluminescence Cell Viability Assay Kit (Promega, Cat#G7572) Black transparent flat-bottomed 96-hole plate (Corning®, Cat# 3603)

[0284] (ii) Instruments SpectraMax Multi-Label Microplate Analyzer MD,2104-0010A; Carbon dioxide incubator, Thermo Scientific 3100 series; Biosafety cabinet, Thermo Scientific, 1300 series, model A2; Inverted microscope, Olympus, CKX41SF; Siemens refrigerator, KK25E76TI.

[0285] (III) Cell lines and culture conditions

[0286] (iv) Experimental Procedure 1. Cell culture and inoculation: (1) Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. Cell viability is assessed using the trypan blue exclusion method to ensure that the cell viability is above 90%. (2) Adjust the cell concentration to achieve the desired final density; add 90 μL of cell suspension to a 96-well plate. (3) Incubate the cells overnight in a 96-well plate at 37°C, 5% CO2 and 95% humidity. 2. T0 baseline data: (1) Add 10 μL of PBS to each well of a T0 plate containing cells. (2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. (3) Add an equal volume of CTG solution to each well. (4) Vibrate on a fixed-track shaker for 5 minutes to lyse the cells. (5) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal. (6) Read the T0 fluorescence signal value. 3. Compound dilution and addition (1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10mM stock solution. (2) Prepare compound solutions diluted 1000 times and 3.16 times. (3) Dilute the 1000× diluted compound solution 100 times with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μM. There are 9 concentrations, diluted 3.16 times. Add 10 μL of the drug solution to each well of a 96-well plate and seed cells. Set up three replicate wells for each compound concentration. The final concentration of DMSO is 0.1%. (4) Place the cells in a 96-well plate containing the drug, and culture at 37°C, 5% CO2 and 95% humidity for 72 hours, and then perform CTG analysis. 4. Fluorescent signal reading (1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. (2) Add an equal volume of CTG solution to each well. (3) Vibrate on a fixed-track shaker for 5 minutes to lyse the cells. (4) Place the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal. (5) Read the fluorescence value. 5. Data Processing

[0287] Data were analyzed using GraphPad Prism 7.0 software, and a nonlinear S-curve regression was used to fit the data to obtain the dose-response curve. The IC50 value (unit: nM) was then calculated based on this curve. Specific experimental results are shown in Table 1.

[0288] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0289] [Table 1: Biological Test Results]

[0290] Based on the bioactivity data of the compounds in the specific embodiments, 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.

[0291] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above disclosure of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof:

1. Wherein, X1 and X2 are each independently N or CH; Y is a bond, O, S, N (R14) or C (R15R16); R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, morpholine, 3-6 member oxocyclic, 3-6 member azacyclic, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and 3-6 member heterocyclic, and the above groups are independently further selected as needed by one or more groups selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, and amino. R2 is substituted by mono-C1-4 alkylamine and di-C1-4 alkylamine substituents; R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, which may be further substituted independently as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups; R5a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, and C3-6 cycloalkyl; R5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, and C3-6 cycloalkyl; R14 is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclic, -S(O)rR8, -C0-4alkyl-O-R9, -C(O)OR9, -C(O)R10, and -C(O)NR11R12; R15 and R16 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, and 3-6 member heterocyclic groups. Alternatively, R15 and R16 together with the carbon atom directly attached to them form a C(O), C3-6 cycloalkyl, or 3-6 member heterocyclic group. The above groups may be further substituted as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6 member heterocyclic groups, and =O.Each R8 is independently selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, and -NR11R12, wherein the above groups are independently and as needed further selected by one or more of deuterium, halogen, hydroxyl, =O, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C The substituents are 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy, and -NR11R12; each R9 is independently selected from hydrogen, deuterium, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6 heterocyclic, C6-8 aryl, and 5-8 heteroaryl, and the above groups are independently further substituted as needed by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3- The substituents are 6-cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryl and -NR11R12; each R10 is selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6- 8-aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR11R12, wherein the above groups are independently and as needed further replaced by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6-membered heterocyclic, 3-6-membered heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR11R12;Each R11 and R12 is independently selected from hydrogen, deuterium, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, C3-6 cycloalkyl, 3-6-membered heterocyclic, C6-8 aryl, 5-8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino. And C1-4 alkyl, wherein the above groups are independently and as needed further selected by one or more of deuterium, halogen, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halosubstituted C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5 The R11 and R12 groups are substituted with a -8-membered heteroaryl group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, or a C1-4 alkylyl group. Alternatively, R11 and R12 together with the nitrogen atom directly attached to them form a 4-8-membered heterocyclic group or a 5-8-membered heteroaryl group, which may be further substituted as needed with one or more substituents selected from deuterium, halogen, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, etc. The substituents are halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 member heterocyclic, 3-6 member heterocyclic, C6-8 aryl, C6-8 aryloxy, 5-8 member heteroaryl, 5-8 member heteroaryl, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and C1-4 alkylacryl; and each r is independently 0, 1, or 2.

2. A compound of formula (III) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and the above groups may be further replaced independently as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteryl, and dideuterylmethyl.

3. A compound of formula (III) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, morpholine, 3-6 member oxocyclic, 3-6 member azacyclic, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy, and the above groups are independently and as needed further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, and cyclopentyl; R5a is hydrogen; R5e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, and dideuterylmethyl.

4. A compound of formula (III) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R14 is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, dideuterylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, and aziridine; R15 and R16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, and piperazine. Alternatively, R15 and R16 together with the carbon atom directly attached to them form a C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, or aziridine group, which may be further substituted as needed by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteryl, dideuterylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, aziridine, and =O.

5. A compound of formula (III) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Selected from the following compounds:

6. A method for preparing a compound of formula (III) as claimed in claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, characterized by comprising the following steps:

6. Wherein, X is chlorine or bromine, and X1, X2, Y, R1, R2, R5a and R5e are as defined in request item 1.

7. A pharmaceutical composition comprising a compound of formula (III) as claimed in any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of formula (III) as claimed in any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of at least part of cancer, tumor or metastatic disease associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

9. Use of a compound of formula (III) as claimed in any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

10. Use of a compound of formula (III) as claimed in any one of claims 1 to 5, its stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of at least a portion of 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, sarcomas, inverted papilloma of the nasal cavity and sinuses, or squamous cell carcinoma of the nasal cavity and sinuses associated with inverted papilloma of the nasal cavity and sinuses.

11. The use as described in claim 10, wherein, The lung cancer is non-small cell lung cancer; the gastrointestinal tumor is stomach 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.

12. The use of a compound of formula (III) as claimed in any one of claims 1 to 5, its stereoisomers or pharmaceutically acceptable salts thereof, for the treatment and / or prevention of at least part of 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, sarcomas, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

13. A compound of formula (III) as claimed in claim 12, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, The lung cancer is non-small cell lung cancer; the gastrointestinal tumor is stomach 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.