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

Abstract

The present invention relates to pyrimidine-4,6-diamine derivatives and their preparation method and pharmaceutical application. In particular, the present invention relates to pyrimidine-4,6-diamine derivatives having a structure represented by formula (I), their preparation method, pharmaceutical composition containing the same, and their use as EGFR inhibitors and their use in the manufacture of drugs for treating and / or preventing cancer, tumor or metastatic diseases at least partly associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, particularly in the manufacture of drugs for treating and / or preventing hyperproliferative diseases and cell death induced disorder diseases. Here, each substituent of formula (I) is defined as in the specification. TIFF2024522832000100.tif5793

Description

[Technical Field]

[0001] The present invention belongs to the field of drug synthesis, specifically to pyrimidine-4,6-diamine derivatives and their preparation methods and pharmaceutical applications. [Background technology]

[0002] Lung cancer is the most common malignant tumor worldwide and poses 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, multiple molecular mechanisms, including gene mutations and abnormal expression, have been identified that lead to the development of NSCLC, of ​​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 389, 299-311, 2017), with East Asians being relatively sensitive, with a mutation frequency of approximately 50% (Passaro, A., Janne, PA, Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377-391, 2021). EGFR activating mutations occur mainly in exons 18 to 21, with deletion mutations in exon 19 (Del19) and the L858R point mutation in exon 21 being the most common mutation isoforms, accounting for more than 80% of all mutations (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 cause ligand-independent receptor activation and promote tumor cell survival and proliferation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) primarily target these two types of activating mutations. Compared with platinum-based chemotherapy, first- and second-generation EGFR TKIs can significantly extend 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, randomized phase 3 trial. The Lancet. Oncology 13, 239-246, 2012); (Sequist, LV 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 tends to emerge 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, randomized 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, randomized controlled trial. The Lancet. Oncology 17, 577-589, 2016). EGFR T790M mutation is the primary mechanism of drug 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 3 FLAURA study, osimertinib demonstrated superior therapeutic 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 378, 113-125, 2018), directly propelling osimertinib into the ranks of first-line treatment plans.

[0003] Although osimertinib has a remarkable therapeutic effect, drug resistance inevitably emerges and causes disease progression. Several EGFR-dependent (on-target) and -independent (off-target) drug resistance mechanisms have been reported in both preclinical and clinical studies (Passaro, A., Janne, PA, Mok, T. et al. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377-391, 2021). According to a phase III FLAURA study, approximately 10–15% of patients treated with osimertinib as a first-line therapy for advanced NSCLC develop EGFR-dependent drug resistance, of which C797S in exon 20 is the most common independent mutation, accounting for 7% of cases (Ramalingam, SS et al. LBA50 Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 2018). The C797S mutation is located in the tyrosine kinase domain of EGFR and prevents osimertinib from forming a covalent bond with the ATP-binding domain of EGFR, resulting in drug resistance. There is no evidence that patients receiving osimertinib as a first-line treatment develop acquired EGFR T790M mutations (Ramalingam, SS et al. LBA50 Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 2018).Therefore, the double mutation consisting of Del19 / L858R and C797S may be one of the important mechanisms of drug resistance when treated with osimertinib as a first-line drug (Tumbrink, HL, Heimsoeth, A. & Sos, ML The next tier of EGFR resistance mutations in lung cancer. Oncogene 40, 1-11, 2021). However, a new generation of EGFR TKIs with high activity and selectivity for the double mutation consisting of Del19 / L858R and C797S may meet the clinical needs of these patients as a new generation of treatment option after drug resistance occurs when treated with osimertinib as a first-line drug. Summary of the Invention

[0004] The object of the present invention is to provide pyrimidine-4,6-diamine derivatives, as well as their preparation methods and pharmaceutical applications. The series of compounds of the present invention have strong inhibitory effects on the cytological activity of EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation, and are highly selective over EGFR wild-type. They are therefore widely applicable to the production of drugs for treating and / or preventing cancers, tumors, or metastatic diseases, at least some of which are associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation, in particular drugs for treating hyperproliferative diseases and cell death-induced disorders. Therefore, the development of a new generation of EGFR inhibitors is desired.

[0005] A first aspect of the present invention provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] (In the formula: X1 and X2 are each independently N or CR7; Z is N or CH; R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, hydroxy group, C 1-10 Alkoxy group, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic oxy group, C 6-10 Aryloxy group, 5-10 membered heteroaryloxy group, -SF5, -S(O) r R8, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 and -C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: R2 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-8 Alkyl-C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0006] R3 and R4 are independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 or R3 and R4 together with the nitrogen atom directly connected thereto form a 4-12 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R10 and optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0007] Each R5 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 or when m≧2, two adjacent R5s therein, together with the moiety directly linked thereto, are selected from the group consisting of 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups, C 6-10 forming an aryl group or a 5-10 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0008] R6 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C0-8 Alkyl-N(R 11 )-C(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0009] Each R7 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 or two R7 together with the moiety directly linked thereto are selected from the group consisting of 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups, C 6-10 forming an aryl group or a 5-10 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10, -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0010] Each R8 is independently hydrogen, deuterium, a hydroxy group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: Each R9 is independently hydrogen, deuterium, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10aryl groups and 5-10 membered heteroaryl groups, said groups independently optionally further containing deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0011] Each R 10 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0012] Each R11 and R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 alkanoyl groups, which groups may independently optionally further comprise deuterium, halogen, hydroxyl groups, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups;

[0013] Alternatively, R 11 and R 12 together with the nitrogen atom directly linked thereto form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group may optionally further contain deuterium, halogen, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; m is 0, 1, 2, 3, 4, or 5, and each r is independently 0, 1, or 2; In a preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, X1 and X2 are each independently N or CR7;

[0014] R1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, hydroxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic oxy group, C 6-8 Aryloxy group, 5-8 membered heteroaryloxy group, -SF5, -S(O) r R8, -C(O)OR9, -C(O)R 10 and -OC(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0015] R2 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0016] R3 and R4 are independently hydrogen, deuterium, a hydroxyl group, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 or R3 and R4 together with the nitrogen atom directly connected thereto form a 4-12 membered monocyclic or polycyclic heterocyclic group, which may optionally further contain deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0017] Each R5 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 or when m≧2, two adjacent R5s therein, together with the moiety directly linked thereto, are selected from the group consisting of 5-8 Cycloalkyl groups, 5-8 membered heterocyclic groups, C6-8 forming an aryl group or a 5-8 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0018] R6 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10, -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of:

[0019] Each R7 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 Alternatively, two R7 together with the moiety directly linked thereto are selected from the group consisting of 5-8 Cycloalkyl groups, 5-8 membered heterocyclic groups, C 6-8forming an aryl group or a 5-8 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: where R8, R9, R 10 , R 11 , R 12 , m and r are as defined for the compound of formula (I).

[0020] In a preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the compound represented by formula (I) is a compound represented by the following formula (II): [ka] (In the formula: X1 and X2 are each independently N or CR7; Z is N or CH; Y is a bond, O, S, N(R 14 ) or C(R 15 R 16 ) and R1 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, hydroxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic oxy group, C 6-8 aryloxy groups and 5-8 membered heteroaryloxy groups, said groups independently optionally further containing deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0021] R2 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 and -C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: R 5a , R 5b , R 5c , R 5d and R 5e are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 selected from the group consisting of

[0022] R6 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 selected from the group consisting of Each R7 is independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 selected from the group consisting of

[0023] R 13a , R 13b , R 13c and R 13d are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C(=NR 11 )R 10 , -C 0-4 Alkyl-N(R11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 or R 13a and R 13b , R 13c and R 13d C(O), C together with the carbon atoms directly connected to them 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclic group, R 14 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 selected from the group consisting of

[0024] R 15 and R 16 are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11)R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 or R 15 and R 16 are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: where R8, R9, R 10 , R 11 , R 12 and r are as described for compounds of formula (I).

[0025] In a more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R2 is hydrogen, deuterium, halogen, a cyano group, C1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups, 5-8 membered heteroaryl groups, and -SF5, which groups may independently optionally further comprise deuterium, halogen, cyano, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: where R8, R9, R 10 , R 11 , R 12 and r are as defined for the compound of formula (I).

[0026] In a more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is hydrogen, deuterium, halogen, a cyano group, C 1-4 Alkyl group, allyl group, vinyl group, ethynyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, hydroxy group, C 1-4 Alkoxy group, C 3-6and 3-6 membered heterocyclic oxy groups, which independently optionally further include deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: R 5a , R 5b , R 5c , R 5d and R 5e are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups; R6 is hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl and deuterium-substituted C 1-4 alkyl groups, Each R7 is independently hydrogen, deuterium, halogen, cyano group, or C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl and deuterium-substituted C 1-4 alkyl groups, where R 11 and R 12 is as described for the compound of formula (I).

[0027] In a more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R 13a , R 13b , R 13c and R 13d are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl groups and C 2-4 alkynyl groups, or R 13a and R 13b , R 13c and R 13d are C(O), C together with the carbon atoms directly connected to them. 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclic group, R 14 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R8, -C 0-4 Alkyl-O-R9, -C(O)OR9, -C(O)R 10 and -C(O)NR 11 R 12 selected from the group consisting of R 15 and R 16 are independently hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups, or R 15 and R 16 are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further comprise deuterium, halogen, cyano, nitro, azido, C 1-4Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups, =O, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: where R8, R9, R 10 , R 11 , R 12 and r are as defined for the compound of formula (I).

[0028] In a preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the compound represented by formula (I) is a compound represented by the following formula (III): [ka] (where, X1 and X2 are each independently N or CH; Y is a bond, O, S, N(R 14 ) or C(R 15 R 16 ) and R1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, morpholinyl, 3- to 6-membered oxacyclyl, 3- to 6-membered azacyclyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and 3- to 6-membered heterocyclic oxy groups, which groups may independently optionally further comprise deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 Alkyl group, C 3-6 Cycloalkyl group, 3-6 membered heterocyclic group, amino group, mono C 1-4 Alkylamino groups and diC 1-4 and optionally substituted by one or more substituents selected from the group consisting of alkylamino groups; R2 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl groups, which groups may independently be optionally further substituted with deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclic groups;

[0029] R 5a represents hydrogen, deuterium, fluorine, chlorine, bromine, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, R 5e represents hydrogen, deuterium, fluorine, chlorine, bromine, cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C1-4 Alkyl groups and C 3-6 cycloalkyl groups, R 14 is hydrogen, deuterium, hydroxyl group, methyl group, ethyl group, propyl group, isopropyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -S(O) r R8, -C 0-4 Alkyl-O-R9, -C(O)OR9, -C(O)R 10 and -C(O)NR 11 R 12 selected from the group consisting of

[0030] R 15 and R 16 are independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups, or R 15 and R 16 are one C(O), C together with the carbon atom directly connected to them. 3-6 forming a cycloalkyl group or a 3-6 membered heterocyclic group, which may optionally further contain deuterium, fluorine, chlorine, bromine, a cyano group, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 optionally substituted by one or more substituents selected from the group consisting of a cycloalkyl group, a 3- to 6-membered heterocyclic group, and =O; However, R8, R9, R 10 , R 11 , R 12 and r are as described for compounds of formula (I).

[0031] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, each R8 is independently hydrogen, deuterium, a hydroxy group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl groups, 5-8 membered heteroaryl groups and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0032] Each R9 is independently hydrogen, deuterium, or C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 aryl groups and 5-8 membered heteroaryl groups, said groups independently optionally further comprising deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0033] Each R 10 is hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of:

[0034] Each R 11 and R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4alkanoyl groups, which groups may independently optionally further comprise deuterium, halogen, hydroxyl groups, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups;

[0035] Alternatively, R 11 and R 12 together with the nitrogen atom directly linked thereto form a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group, and the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group may optionally further contain deuterium, halogen, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkanoyl groups.

[0036] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R2 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an azetidinyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, and a triazolyl group, and the groups may be independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, a cyano group, a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, a trideuteromethyl group, and a dideuteromethyl group;

[0037] In a more preferred embodiment, in the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a morpholinyl group, a 3- to 6-membered oxacyclyl group, a 3- to 6-membered azacyclyl group, a hydroxy group, a methoxy group, an ethoxy group, an isopropoxy group, a cyclopropoxy group, and a cyclobutoxy group, and the groups may be independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group;

[0038] R 5a is hydrogen, R 5e is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, and diduteromethyl; In a more preferred embodiment, in the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R 14is selected from the group consisting of hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, and azetidinyl; R 15 and R 16 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; or R 15 and R 16 together with the carbon atom directly linked thereto form a C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl group, which may optionally be further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl and ═O.

[0039] In the most preferred form, the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds: [ka] [ka] [ka] [ka] [ka]

[0040] A second aspect of the present invention provides a process for producing a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps: [ka] (wherein X is chlorine or bromine, and X1, X2, Z, R1, R2, R3, R4, R5, R6 and m are as defined for the compound of formula (I)).

[0041] 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.

[0042] The present invention further relates to the use of the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing cancer, tumor, or metastatic disease associated, at least in part, with the EGFR Del19 mutation, the EGFR L858R mutation, the EGFR L858R / C797S double mutation, or the EGFR Del19 / C797S double mutation.

[0043] The present invention further relates to the use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders. The present invention further relates to use of the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal cavity and paranasal sinus inverted papilloma, or nasal cavity and paranasal sinus squamous cell carcinoma associated with nasal cavity and paranasal sinus inverted papilloma, at least some of which are associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation.

[0044] The present invention further relates to a compound represented by the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use as a drug.

[0045] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer, tumor, or metastatic disease, at least some of which are associated with the EGFR Del19 mutation, the EGFR L858R mutation, the EGFR L858R / C797S double mutation, or the EGFR Del19 / C797S double mutation.

[0046] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is used for preventing and / or treating tumors, cancers, and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders.

[0047] The present invention further relates to a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in preventing and / or treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal cavity and paranasal sinus inverted papilloma, or nasal cavity and paranasal sinus squamous cell carcinoma associated with nasal cavity and paranasal sinus inverted papilloma, at least some of which are associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation.

[0048] The present invention further relates to a method for treating and / or preventing cancer, tumor or metastatic disease associated at least in part with the EGFR Del19 mutation, the EGFR L858R mutation, the EGFR L858R / C797S double mutation or the EGFR Del19 / C797S double mutation, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0049] The present invention further relates to a method for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0050] The present invention further relates to a method for treating and / or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal cavity and paranasal sinus inverted papilloma or nasal cavity and paranasal sinus squamous cell carcinoma associated with nasal cavity and paranasal sinus inverted papilloma, at least some of which are associated with the EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0051] Specific Embodiments As a result of extensive and in-depth research, the inventors of the present application have for the first time developed pyrimidine-4,6-diamine derivatives having the structure represented by the following formula (I): The series of compounds of the present invention are widely applicable to the manufacture of drugs for treating and / or preventing cancer, tumor, or metastatic diseases, at least some of which are associated with the EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, or EGFR Del19 / C797S double mutation, particularly for treating hyperproliferative diseases and cell death-induced disorders. The development of a new generation of EGFR inhibitors is therefore desired. Based on this, the present invention has been completed.

[0052] Special Note: Unless stated to the contrary or otherwise specified, terms used in the following specification and claims have the following meanings:

[0053] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, and is preferably a linear alkyl group or a branched alkyl group containing 1 to 10 or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and is particularly preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 5-methylpentyl group, a 6-methylpentyl group, a 7-methylpentyl group, a 8-methylpentyl group, a 9-methylpentyl group, a 10-methylpentyl group, a 11-methylpentyl group, a 12-methylpentyl group, a 13-methylpentyl group, a 14-methylpentyl group, a 15-methylpentyl group, a 16-methylpentyl group, a 17-methylpentyl group, a 18-methylpentyl group, a 21-methylpentyl group, a 22-methylpentyl group, a 23-methylpentyl group, a 24-methylpentyl group, a 25-methylpentyl group, a 26-methylpentyl group, a 27-methylpentyl group, a 28-methylpentyl group, a 29-methylpentyl group, a 30-methylpent Examples of alkyl groups include, but are not limited to, octyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, and various branched chain isomers thereof. 1-10 "Alkyl group" refers to straight chain alkyl groups and branched chain alkyl groups containing 1 to 10 carbon atoms, and "C 1-4 "Alkyl group" refers to a straight chain alkyl group and a branched chain alkyl group containing 1 to 4 carbon atoms. 0-8 "Alkyl group" refers to a straight chain alkyl group and a branched chain alkyl group containing 0 to 8 carbon atoms. 0-4 "Alkyl group" refers to straight chain and branched chain alkyl groups containing 0 to 4 carbon atoms.

[0054] The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0055] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may contain one or more (preferably one, two, or three) double bonds, but does not contain any ring with a completely conjugated π-electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, and is preferably a cycloalkyl group containing 3 to 12, 3 to 8, or 3 to 6 carbon atoms, such as "C 3-12 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 12 carbon atoms, and "C 3-6 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, and "C 5-10 "Cycloalkyl group" refers to a cycloalkyl group containing 5 to 10 carbon atoms, and "C 5-8 "Cycloalkyl group" refers to a cycloalkyl group containing 5 to 8 carbon atoms, wherein: Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0056] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share one carbon atom (called a spiro atom) between monocyclic rings; these groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a fully conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, dispirocycloalkyl groups, or polyspirocycloalkyl groups, and spirocycloalkyl groups include, but are not limited to: [ka]

[0057] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of which may contain one or more (preferably one, two, or three) double bonds, but none of which has a completely conjugated pi-electron system. Depending on the number of constituent rings, fused cycloalkyl groups may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, and fused cycloalkyl groups include, but are not limited to: [ka]

[0058] "Bridged cycloalkyl groups" refer to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected, and these groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated pi-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups include, but are not limited to: [ka]

[0059] The ring of the cycloalkyl group may be fused to the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like.

[0060] Cycloalkyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0061] "Heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may contain one or more (preferably one, two, or three) double bonds, but which does not have a single ring with a completely conjugated pi-electron system, and in which one or more (preferably one, two, three, or four) ring atoms in the heterocyclic group are nitrogen, oxygen, S(O)(=NH) or S(O) r(wherein r is an integer of 0, 1, or 2), but does not include a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, and is preferably a heterocyclic group containing 3 to 12, or 3 to 8, or 3 to 6, or 5 to 6 ring atoms; for example, a "3- to 6-membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, and a "3- to 12-membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms. "4- to 8-membered heterocyclic group" refers to a ring group containing 4 to 8 ring atoms, "4- to 10-membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, "4- to 12-membered heterocyclic group" refers to a ring group containing 4 to 12 ring atoms, "5- to 6-membered heterocyclic group" refers to a ring group containing 5 to 6 ring atoms, "5- to 8-membered heterocyclic group" refers to a ring group containing 5 to 8 ring atoms, and "5- to 10-membered heterocyclic group" refers to a ring group containing 5 to 10 ring atoms.

[0062] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, homopiperazyl, and the like.

[0063] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the monocyclic rings, and one or more (preferably 1, 2, 3, or 4) of the ring atoms are 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 groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a fully conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are divided into monospiroheterocyclic groups, dispiroheterocyclic groups, or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to: [ka]

[0064] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more (preferably one, two, three, or four) rings optionally containing one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated pi-electron system, and one or more (preferably one, two, three, or four) ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (wherein r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, fused heterocyclic groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and fused heterocyclic groups include, but are not limited to: [ka]

[0065] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and these groups may contain one or more (preferably one, two, or three) double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more (preferably one, two, three, or four) of the ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (wherein r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclic groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and bridged heterocyclic groups include, but are not limited to, the following: [ka]

[0066] The ring of the heterocyclic group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to: [ka]

[0067] Heterocyclic groups may be optionally substituted or unsubstituted, and if substituted, the substituents may independently be deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0068] An "aryl group" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably an all-carbon aryl group containing 6 to 10, or 6 to 8, or 6 carbon atoms, such as "C 6-10 "Aryl group" refers to an all-carbon aryl group containing 6 to 10 carbon atoms, and "C 6-8 "Aryl" refers to an all-carbon aryl group containing 6 to 8 carbon atoms, including, but not limited to, phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring, including, but not limited to: [ka]

[0069] The "aryl group" may be substituted or unsubstituted, and when substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0070] The term "heteroaryl" refers to a heteroaromatic group containing one or more (preferably 1, 2, 3, or 4) heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, or 2) heteroatoms, preferably 5-10, 5-8, or 5-6 ring atoms. For example, a "5-8-membered heteroaryl group" refers to a heteroaromatic group containing 5-8 ring atoms, and a "5-10-membered heteroaryl group" refers to a heteroaromatic group containing 5-10 ring atoms, including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The ring of the heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including, but not limited to: [ka]

[0071] The "heteroaryl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0072] The term "alkenyl group" refers to an alkyl group as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a straight-chain or branched-chain alkenyl group containing 2 to 10 or 2 to 4 carbon atoms, such as "C 2-10 "Alkenyl group" refers to a straight-chain or branched-chain alkenyl group containing 2 to 10 carbon atoms, and "C 2-4 The term "alkenyl group" refers to a straight-chain or branched-chain alkenyl group containing 2 to 4 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0073] The "alkenyl group" may be substituted or unsubstituted, and when substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0074] The term "alkynyl group" refers to an alkyl group as defined above, which consists of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a straight-chain or branched-chain alkynyl group containing 2 to 10 or 2 to 4 carbon atoms, such as "C 2-10"Alkynyl group" refers to a straight-chain or branched-chain alkynyl group containing 2 to 10 carbon atoms, and "C 2-4 The term "alkynyl group" refers to a straight or branched chain alkynyl group containing 2 to 4 carbon atoms, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0075] The "alkynyl group" may be substituted or unsubstituted, and when substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0076] "Alkoxy group" refers to an -O-alkyl group, where alkyl is as defined above, for example, "C 1-10 "Alkoxy group" refers to an alkyloxy group containing 1 to 10 carbon atoms, and "C 1-4 "Alkoxy" refers to alkyloxy groups containing 1 to 4 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0077] The "alkoxy group" may be optionally substituted or unsubstituted, but when substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0078] "Cycloalkoxy group" refers to an -O-cycloalkyl group, where cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkoxy group" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms, and "C 3-8 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3 to 8 carbon atoms, including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

[0079] The "cycloalkoxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0080] "Heterocycleoxy" refers to an -O-heterocycle, where heterocycle is as defined above, including, but not limited to, azetidinyloxy, oxetanyloxy, azacyclopentyloxy, azacyclohexyloxy, oxacyclohexyloxy, and the like.

[0081] The "heterocyclic oxy group" may be optionally substituted or unsubstituted, but when substituted, the substituents are independently deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C(=NR 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10, -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Preferred are one or more (preferably one, two, three or four) substituents selected from the group consisting of:

[0082] "C 1-10 The alkanoyl group is C 1-10 It refers to the monovalent atomic group remaining after removing the hydroxy group from an alkyl acid, and is usually also expressed as "C0-9 alkyl-C(O)-". For example, "C1 alkyl-C(O)-" refers to an acetyl group, "C2 alkyl-C(O)-" refers to a propionyl group, and "C3 alkyl-C(O)-" refers to a butyryl or isobutyryl group.

[0083] "C 1-4 " is "C 1-4 "C alkyl group" 0-4 " is "C 0-4 "C alkyl group" 1-8 " is "C 1-8 "C alkyl group" 0-8 " is "C 0-8 "alkyl group" is defined above.

[0084] "-C 0-8 Alkyl-S(O) r R8" is -S(O) r The sulfur atom in R8 is C 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0085] "-C 0-8 Alkyl-O-R9" is an alkyl group in which the oxygen atom in -O-R9 is C. 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0086] "-C 0-8Alkyl-C(O)OR9 is a group in which the carbonyl group in -C(O)OR9 is C 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0087] "-C 0-8 Alkyl-C(O)R 10 " is -C(O)R 10 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0088] "-C 0-8 Alkyl-OC(O)R 10 " is -OC(O)R 10 The oxygen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0089] "-C 0-8 Alkyl-NR 11 R 12 " is -NR 11 R 12 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0090] "-C 0-8 Alkyl-C(=NR 11 )R 10 " is -C(=NR 11 )R 10 The carbon atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0091] "-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 " is -N(R 11 )-C(=NR 12 )R 10The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0092] "-C 0-8 Alkyl-C(O)NR 11 R 12 " is -C(O)NR 11 R 12 The carbonyl group in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0093] "-C 0-8 Alkyl-N(R 11 )-C(O)R 10 " is -N(R 11 )-C(O)R 10 The nitrogen atom in 0-8 It refers to a group linked to an alkyl group, C 0-8 The alkyl group is as defined above.

[0094] Halogen-substituted C 1-10 The term "alkyl group" refers to an alkyl group having 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced with a fluorine, chlorine, bromine, or iodine atom, and includes, but is not limited to, difluoromethyl (-CHF2), dichloromethyl (-CHCl2), dibromomethyl (-CHBr2), trifluoromethyl (-CF3), trichloromethyl (-CCl3), tribromomethyl (-CBr3), etc.

[0095] Halogen-substituted C 1-10 The term "alkoxy group" refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogen atoms in the alkyl group are optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Examples include, but are not limited to, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, and a tribromomethoxy group.

[0096] Deuterium-substituted C 1-10The term "alkyl group" refers to an alkyl group having 1 to 10 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced with a deuterium atom. Examples include, but are not limited to, monodeuteromethyl (-CH2D), dideuteromethyl (-CHD2), trideuteromethyl (-CD3), and the like.

[0097] Deuterium-substituted C 1-10 The term "alkoxy group" refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogen atoms in the alkyl group are optionally substituted with deuterium atoms. Examples include, but are not limited to, a monodeuteromethoxy group, a diduteromethoxy group, a trideuteromethoxy group, and the like.

[0098] "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.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and this description includes both the case where the event or circumstance occurs and the case where it does not occur, i.e., the two cases of substituted and unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.

[0100] "Substitution" means that one or more "hydrogen atoms" in a group are independently replaced with a corresponding number of substituents. Of course, the substituents are only in these chemically possible positions, and are in accordance with the chemical valence bond theory, so that a person skilled in the art can easily confirm (through experiment or theory) whether the substitution is possible or not. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (e.g., an olefin).

[0101] The English term "stereoisomer" refers to an isomer formed by differences in the spatial arrangement of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers formed by the rotation of a single bond are called conformational isomers, sometimes called rotamers. Stereoisomers formed by bond length, bond angles, or the presence of double bonds or rings in the molecule are called configurational isomers, which are further divided into two types. Isomers formed because the double bonds or single bonds of ring carbon atoms cannot freely rotate are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers, and when a compound of the present invention contains a double bond, it may be understood to include the E-form and / or the Z-form unless otherwise specified. Stereoisomers with different optical rotations formed due to the lack of antiaxial symmetry in the molecule are called optical isomers and are divided into R and S configurations. Unless otherwise specified, the "stereoisomer" described in the present invention may be understood to include one or more of the enantiomers, configurational isomers, and conformational isomers.

[0102] The term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0103] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, and other components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and contribute to the absorption of the active ingredients to exert their biological activity.

[0104] The present invention will be explained in more detail and comprehensively below in conjunction with examples, but the present invention is in no way limited to the contents of the examples.

[0105] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (MeOH-d), and deuterated chloroform (CDCl), and the internal standard was tetramethylsilane (TMS).

[0106] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 6120 mass spectrometer, and HPLC measurements were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150 × 4.6 mm column).

[0107] The silica gel plates used for thin-layer chromatography were Yantai Yellow Sea HSGF254 or Qingdao GF254, with a 0.15-0.20 mm diameter for TLC and a 0.4-0.5 mm diameter for thin-layer chromatography product separation and purification. For column chromatography, Yantai Yellow Sea silica gel with a 200-300 mesh diameter was generally used as the support.

[0108] The starting materials in the examples of the present invention are known and commercially available or can be synthesized by or according to methods known in the art.

[0109] Unless otherwise specified, all reactions of this invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and reaction temperatures are in degrees Celsius (°C).

[0110] 1. Manufacturing of intermediates Intermediate 1: Preparation of 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0111] First step: Synthesis of 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] 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 added to DMSO (25 mL) and stirred overnight at 80 °C under nitrogen gas 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, the mixture was separated by column chromatography to give 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] + .

[0112] Second step: Synthesis of 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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), vented with hydrogen gas, and then stirred at room temperature under atmospheric hydrogen gas for 1 hour. Upon completion of the reaction, the mixture was filtered, and the filtrate was concentrated and separated by column chromatography to give 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] + .

[0113] Preparation of Intermediate 2: 2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline [ka]

[0114] First step: Synthesis of 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine [ka] 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.73 g, 3.94 mmol) was added to DMSO (20 mL), followed by the addition of K2CO3 (1.09 g, 7.89 mmol) and 4-(piperidin-4-yl)morpholine (0.81 g, 4.73 mmol). The mixture was allowed to react at 80 °C overnight, then heated to 110 °C for 5 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography [eluent: CHCl2 / MeOH (+1% aqueous ammonia) = 0-10%] to obtain 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine (1.23 g, yield: 80.9%). MS m / z (ESI): 336.0 [M+H] + .

[0115] Second step: Synthesis of 2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline [ka] 4-(1-(5-Methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)morpholine (1.23 g, 3.18 mmol) was dissolved in methanol (10 mL), Pd / C (0.10 g, 10%) was added, and the mixture was purged with hydrogen gas three times. The mixture was then reacted overnight at room temperature under atmospheric hydrogen gas. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting crude product was separated by column chromatography [eluent: CHCl / MeOH (+1% aqueous ammonia) = 0-10%] to give 2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.81 g, 80.2% yield). MS m / z (ESI): 306.2 [M+H] + .

[0116] Preparation of Intermediate 3: 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0117] First step: Synthesis of 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene [ka] 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 stirring overnight. After completion of the reaction, 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, 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, 90.2% yield) was obtained. MS m / z (ESI): 200 [M+H] + .

[0118] Second step: Synthesis of 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] 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), and the mixture was stirred at 90 °C overnight. After the reaction was complete, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (700 mg, yield: 91.6%) was obtained. MS m / z (ESI): 363 [M+H] + .

[0119] Third step: Synthesis of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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), followed by the addition of NHCl (1.03 g, 19.31 mmol) and Fe powder (1.08 g, 19.31 mmol) and stirring at 85°C for 2 hours. After the reaction was completed, it was filtered and the filtrate was concentrated. The crude product was separated by column chromatography to give 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] + .

[0120] Preparation of Intermediate 4: 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0121] First step: Synthesis of 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene [ka] 5-Fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), Na2CO3 (743 mg, 7.01 mmol) was added, and the reaction mixture was heated to 90 °C. ClCF2CO2Na (1247 mg, 8.18 mmol) was added, and the mixture was stirred at 90 °C for 3 hours. After completion of the reaction, 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, 92.9% yield). MS m / z (ESI): 222.0 [M+H] + .

[0122] Second step: Synthesis of 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] 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), and the mixture was stirred at 90 °C overnight. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (760 mg, yield: 91.1%) was obtained. MS m / z (ESI): 385.0 [M+H] + .

[0123] Third step: Synthesis of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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), followed by the addition of NHCl (1057 mg, 19.77 mmol) and Fe powder (1104 mg, 19.77 mmol) and stirring at 85°C for 2 hours. After the reaction was completed, it 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] + .

[0124] Preparation of Intermediate 5: 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline [ka]

[0125] First step: Synthesis of 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene [ka] 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-trifluoroethyl trifluoromethanesulfonate (0.67 mL, 4.68 mmol) and stirring overnight at room temperature. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (560 mg, yield: 94.6%) was obtained. MS m / z (ESI): 254.0 [M+H] + .

[0126] Second step: Synthesis of 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine [ka] 1-Fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (580 mg, 2.29 mmol) was dissolved in DMSO (15 mL), K2CO3 (792 mg, 5.73 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (630 mg, 3.44 mmol) were added, and the mixture was stirred at 90 °C for 6 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine (900 mg, yield: 94.3%) was obtained. MS m / z (ESI): 417.0 [M+H] + .

[0127] Third step: Synthesis of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline [ka] 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), followed by the addition of NHCl (1156 mg, 21.61 mmol) and Fe powder (1207 mg, 21.61 mmol) and stirring at 85°C for 2 hours. After the reaction was completed, it was filtered and the filtrate was concentrated. The crude product was separated by column chromatography to give 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] + .

[0128] Intermediate 6: Preparation of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0129] First step: Synthesis of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.40 g, 5.60 mmol) was dissolved in dimethylamine (10.0 mL), and K2CO3 (1.55 g, 11.20 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.54 g, 8.40 mmol) were added. The mixture was heated to 100 °C under nitrogen gas protection for 2 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 and concentrated. The crude product was separated by column chromatography to give 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] + .

[0130] Second step: Synthesis of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine [ka] 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). Potassium vinyltrifluoroborate (259 mg, 1.94 mmol), Na2CO3 (308 mg, 2.90 mmol), and Pd(dppf)Cl2 (70.8 mg, 0.10 mmol) were then added and the mixture was stirred at 90 °C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction mixture was concentrated, and the crude product was separated by column chromatography to give 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, 86.0% yield). MS m / z (ESI): 361.0 [M+H] + .

[0131] Third step: Synthesis of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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 under atmospheric hydrogen gas for 2 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to give 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] + .

[0132] Preparation of Intermediate 7: 5-Isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0133] First step: Synthesis of 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidin-4-yl)-4-methylpiperazine [ka] 1-(1-(2-Bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) was dissolved in 1,4-dioxane (10 mL) and water (3 mL). Na2CO3 (0.30 g, 2.83 mmol), Pd(dppf)Cl2 (0.03 g, 0.05 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.20 mL, 1.04 mmol) were added and the mixture was heated to 90 °C under nitrogen gas protection overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was washed with saturated brine and dried over sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography to give 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] + .

[0134] Second step: Synthesis of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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 mixture was reacted at room temperature under atmospheric pressure and hydrogen gas for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The resulting crude product was separated by column chromatography [eluent: CHCl / MeOH (+1% aqueous 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] + .

[0135] Preparation of Intermediate 8: 5-Cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0136] First step: Synthesis of 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] To a solution of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) in toluene (10 mL), KPO (0.60 g, 2.83 mmol), tricyclohexylphosphine (0.079 g, 0.28 mmol), Pd(OAc) (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 under nitrogen gas protection overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. 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 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] + .

[0137] Second step: Synthesis of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 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). Iron powder (0.18 g, 3.23 mmol) and NHCl (0.35 g, 6.47 mmol) were added, and the mixture was heated to 70°C under nitrogen gas protection for 2 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated. The crude product obtained was purified by column chromatography to give 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.21 g, 89.2% yield). MS m / z (ESI): 345.2 [M+H] + .

[0138] Preparation of Intermediate 9: 2-Methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinoaniline [ka]

[0139] First step: Synthesis of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyridine [ka] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (900 mg, 3.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine (1.12 g, 5.4 mmol), K2CO3 (1.49 g, 10.8 mmol), and Pd(dppf)Cl2 (263 mg, 0.36 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL) and heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to give 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyridine (900 mg, yield: 99.5%). MS m / z (ESI): 252.1 [M+H] + .

[0140] Second step: Synthesis of 4-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)morpholine [ka] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyridine (150 mg, 0.60 mmol), K2CO3 (247.6 mg, 1.80 mmol), and morpholine (104 mg, 1.19 mmol) were added to DMSO (10 mL) and heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was further 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 give 4-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)morpholine (160 mg, 84.2% yield). MS m / z (ESI): 319.1 [M+H] + .

[0141] Third step: Synthesis of 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinoaniline [ka] 4-(5-Methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)morpholine (160 mg, 0.52 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (20 mg) was added. The mixture was stirred at room temperature for 30 minutes under atmospheric hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to give 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinoaniline (106 mg, yield: 68.3%). MS m / z (ESI): 289.1 [M+H] + .

[0142] Preparation of Intermediate 10: 2-Methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-methylpiperazin-1-yl)aniline [ka]

[0143] First step: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)-4-methylpiperazine [ka] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyridine (150 mg, 0.60 mmol), K2CO3 (248 mg, 1.80 mmol), and N-methylpiperazine (119 mg, 1.19 mmol) were added to DMSO (10 mL) and heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was further washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by column chromatography to give 1-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, yield: 75.8%). MS m / z (ESI): 332.1 [M+H] + .

[0144] Second step: Synthesis of 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-methylpiperazin-1-yl)aniline [ka] 1-(5-Methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, 0.45 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (20 mg) was added. The mixture was stirred at room temperature under atmospheric hydrogen gas for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to give 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-methylpiperazin-1-yl)aniline (68 mg, yield: 50.3%). MS m / z (ESI): 302.1 [M+H] + .

[0145] Preparation of Intermediate 11: 2-Methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka]

[0146] First step: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyridine (0.30 g, 1.19 mmol) was dissolved in dimethylamine (5 mL), and K2CO3 (0.50 g, 3.58 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (0.88 g, 4.78 mmol) were added. The mixture was heated to 100 °C under nitrogen gas protection for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was purified by column chromatography to give 1-(1-(5-methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.23 g, yield: 44.7%). MS m / z (ESI): 415.2 [M+H] + .

[0147] Second step: Synthesis of 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] 1-(1-(5-Methoxy-2-(1-methyl-1H-pyridin-4-yl)-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.23 g, 0.53 mmol) was dissolved in methanol (10 mL), 10% Pd / C (0.10 g) was added, and the mixture was vented with hydrogen gas. The mixture was then left under atmospheric hydrogen gas atmosphere at room temperature overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was then separated by column chromatography to give 2-methoxy-5-(1-methyl-1H-pyridin-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] + .

[0148] Preparation of Intermediate 12: 5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl)aniline [ka]

[0149] First step: Synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene [ka] While cooling in an ice-water bath, 1,2-difluoro-4-methoxybenzene (1.626 mL, 13.88 mmol) was added to concentrated H2SO4 (6.81 g, 69.39 mmol) at 0 °C, and concentrated HNO3 (1.37 g, 15.27 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the reaction mixture was poured into ice water, extracted with EtOAc, and the organic phase was washed with saturated aqueous NaHCO3 and saturated NaCl. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was separated by silica gel column chromatography to give 1,2-difluoro-4-methoxy-5-nitrobenzene (1.14 g, 6.00 mmol, yield: 43.3%).

[0150] Second step: Synthesis of 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] A solution of 1,2-difluoro-4-methoxy-5-nitrobenzene (1.14 g, 6.00 mmol) in 1,4-dioxane (10 mL) was added with 1-methyl-4-(piperidin-4-yl)piperazine (1.10 g, 6.00 mmol) and DIPEA (1.94 g, 14.99 mmol). The mixture was heated to 100 °C under N2 protection and stirred for 2 hours. Upon completion, the mixture was cooled to room temperature. The reaction mixture was concentrated to give the crude product, 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridin-4-yl]-4-methylpiperazine, which was used directly in the next reaction.

[0151] Third step: Synthesis of 5-fluoro-2-methoxy-4-[4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl]aniline [ka] The crude 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridin-4-yl]-4-methylpiperazine (2.26 g, 5.99 mmol) was added to methanol (8 mL) and water (2 mL), and then Fe powder (1.67 g, 29.95 mmol) and NH₄Cl (3.20 g, 59.90 mmol) were added. Under N₂ protection, the mixture was heated to 75°C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was added to aqueous ammonia, followed by extraction with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was 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] + .

[0152] Preparation of Intermediate 13: 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] Synthesized from 1-chloro-2-fluoro-4-methoxybenzene by referring to the preparation method of intermediate 12. MS m / z (ESI): 339.2 [M+H] + .

[0153] Preparation of Intermediate 14: 2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] Prepared using 1,4-dichloro-2-fluorobenzene with reference to the preparation method of intermediate 12. MS m / z (ESI): 343.2 [M+H] + .

[0154] Preparation of Intermediate 15: 2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] Produced using 1-chloro-5-fluoro-4-methyl-2-nitrobenzene with reference to the production method of intermediate 1. MS m / z (ESI): 323.2 [M+H] + .

[0155] Preparation of Intermediate 16: 4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylaniline [ka] Produced by referring to the production method of Intermediate 1. MS m / z (ESI): 333.2 [M+H] + .

[0156] II. Manufacture of specific embodiments 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 [ka]

[0157] First step: Synthesis of 2-(2-fluorophenyl)pyridin-4-amine [ka] 2-Bromopyridin-4-amine (10 g, 57.80 mmol) and (2-fluorophenyl)boronic acid (9.70 g, 69.36 mmol) were dissolved in 1,4-dioxane (170 mL), and aqueous Na2CO3 (2 M, 86.7 mL, 173.40 mmol) and Pd(PPh3)4 (1.34 g, 1.16 mmol) were added. The reaction mixture was purged with nitrogen gas three times, then heated to 90 °C and stirred for 18 h. After completion of the reaction, the mixture was cooled to room temperature, saturated brine (600 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by column chromatography [eluent: EtOAc / PE = 0-50%] to give 2-(2-fluorophenyl)pyridin-4-amine (10.0 g, yield: 92%). MS m / z (ESI): 189.0 [M+H] + .

[0158] Second step: Synthesis of 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine [ka] 2-(2-Fluorophenyl)pyridin-4-amine (5 g, 26.57 mmol) was dissolved in DMF (50 mL). 60% NaH (1.59 g, 39.85 mmol) was added while cooling in an ice-water bath. The mixture was stirred at room temperature for 1 hour. 4,6-Dichloropyrimidine (4.75 g, 31.88 mmol) was added while cooling in an ice-water bath, and then stirred at room temperature overnight. The reaction mixture was quenched with ethanol and concentrated. The crude product was separated by column chromatography to give 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (1 g, 12.5% ​​yield). MS m / z (ESI): 301.2 [M+H] + .

[0159] Third step: N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6Synthesis of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine [ka] 6-Chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (50 mg, 0.17 mmol) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (63.5 mg, 0.2 mmol) were added to ethylene glycol monomethyl ether (3 mL), and 4 M HCl / dioxane solution (0.17 mL, 0.67 mmol) was added, and the mixture was stirred at 120 °C overnight. The reaction mixture was neutralized with NH3 / MeOH solution, concentrated, and then separated by reverse phase column chromatography to obtain N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (21.5 mg, yield: 22.9%) was obtained. MS m / z (ESI): 583.2 [M+H] + .

[0160] 1 H NMR (400 MHz, MeOH-d4) δ 8.27 (d, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.64-6.59 (m,2H), 7.39-7.33 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.15-7.09 (m, 2H), 6.66 (s, 1H), 5.95 (s, 1H), 3.72 (s, 3H), 3.08 (d, J = 11.9 Hz, 2H), 2.65-2.53 (m, 6H), 2.48-2.41 (m, 4H), 2.31-2.5 (m,1H), 2.22 (s, 3H), 2.14 (s, 3H), 1.94-1.88 (m, 2H), 1.65-1.56 (m, 2H).

[0161] 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 [ka] 2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.24 g, 0.76 mmol) and 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (0.20 g, 0.64 mmol) were added to t-butanol (10 mL), and p-toluenesulfonic acid monohydrate (0.60 g, 3.18 mmol) was added. The mixture was heated to 100°C and reacted for 36 hours. The reaction mixture was cooled to room temperature, neutralized with aqueous ammonia, and concentrated. The crude product was separated by column chromatography to obtain N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)phenyl)pyrimidine-4,6-diamine (80 mg, yield: 41.1%) was obtained. MS m / z (ESI): 570.2 [M+H] + .

[0162] 1HNMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.2 Hz, 1H), 7.52-7.41 (m, 1H), 7.36-7.26 (m, 2H), 7.21 (s, 1H), 6.72 (s, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 3.59 (t, J = 4.6 Hz, 4H), 3.11 (d, J = 11.5 Hz, 2H), 2.92 (s, 2H), 2.64 (t, J = 11.5 Hz, 2H), 2.35-2.21 (m, 2H), 2.17 (s, 3H), 1.99 (dt, J = 13.2, 7.0 Hz, 1H), 1.89 (d, J = 11.6 Hz, 2H), 1.64-1.49 (m, 2H).

[0163] 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 [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (180 mg, 0.60 mmol) and 2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (219 mg, 0.66 mmol), NaO tBu (115 mg, 1.20 mmol) and BrettPhos Pd-G3 (109 mg, 0.12 mmol) were added to toluene (10 mL) and heated to 90 °C under nitrogen gas protection and stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated and then separated by column chromatography to obtain the crude product. The crude product was further separated by a preparative column and purified by N 4 -(2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (65 mg, yield: 18.0%) was obtained. MS m / z (ESI): 597.3 [M+H] + .

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.28 (d, J = 15.0 Hz, 2H), 7.99 (s, 1H), 7.91 (td, J = 7.9, 1.8 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.49-7.44 (m, 1H), 7.37-7.26 (m, 2H), 7.17 (s, 1H), 6.70 (s, 1H), 5.91 (s, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.43-3.38 (m, 2H), 3.09 (d, J = 11.4 Hz, 2H), 2.61 (t, J = 11.5 Hz, 4H), 2.39-2.26 (m, 5H), 2.16 (s, 3H), 2.15 (s, 3H), 1.85 (d, J = 11.8 Hz, 2H), 1.62-1.51 (m, 2H), 1.24 (t, J = 6.9 Hz, 3H).

[0165] Example 4: N 4 -(2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6Preparation of -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (200 mg, 0.67 mmol) and 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (259 mg, 0.73 mmol), NaO t Bu (128 mg, 1.33 mmol) and BrettPhos Pd-G3 (121 mg, 0.13 mmol) were placed in toluene (10 mL) and stirred overnight at 90 °C under nitrogen gas protection. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. The crude product was further separated by a preparative column. 4 -(2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (25 mg, yield: 6.1%) was obtained. MS m / z (ESI): 619.3 [M+H] + .

[0166] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.65 (s, 1H), 8.44 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.50-7.44 (m, 1H), 7.36-7.26 (m, 3H), 7.21 (s, 0.25H), 7.03 (s, 0.5H), 6.84 (d, J = 3.2 Hz, 1.25H), 5.98 (s, 1H), 3.11 (d, J = 11.4 Hz, 2H), 2.59 (td, J = 11.9, 2.2 Hz, 4H), 2.41-2.26 (m, 5H), 2.22 (s, 3H), 2.15 (s, 3H), 1.86 (d, J = 11.0 Hz, 2H), 1.64-1.52 (m, 2H).

[0167] 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 [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (53 mg, 0.18 mmol) and 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (68 mg, 0.18 mmol), NaO tBu (34 mg, 0.35 mmol) and BrettPhos Pd-G3 (16 mg, 0.02 mmol) were added to toluene (10 mL) and stirred overnight at 90 °C under nitrogen gas protection. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated by a preparative column to obtain the crude product. 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrimidine-4,6-diamine (1.2 mg, yield: 1%) was obtained. MS m / z (ESI): 651.4 [M+H] + .

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.43 (t, J = 2.8 Hz, 2H), 8.25 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.91 (td, J = 7.9, 2.0 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (td, J = 5.6, 2.6 Hz, 1H), 7.31 (dd, J = 9.3, 6.9 Hz, 2H), 7.16 (s, 1H), 6.84 (s, 1H), 5.88 (s, 1H), 4.68 (q, J = 8.9 Hz, 2H), 3.11 (d, J = 11.5 Hz, 2H), 2.92 (s, 2H), 2.68-2.60 (m, 3H), 2.39-2.27 (m, 6H), 2.18 (s, 3H), 2.15 (s, 3H), 2.05-1.94 (m, 2H), 1.86 (d, J = 12.1 Hz, 2H), 1.64-1.53 ​​(m, 2H).

[0169] Example 6: N 4 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6Preparation of -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.33 mmol) and 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (122 mg, 0.37 mmol), NaO t Bu (63.9 mg, 0.67 mmol) and BrettPhos Pd-G3 (60.3 mg, 0.07 mmol) were added to toluene (10 mL) and stirred overnight at 90 °C under nitrogen gas protection. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product. The crude product was further separated by a preparative column and purified with N 4 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (38 mg, yield: 19.2%) was obtained. MS m / z (ESI): 597.3 [M+H] + .

[0170] 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.47-8.36 (m, 2H), 8.26 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.6, 2.1 Hz, 1H), 7.51-7.41 (m, 1H), 7.37-7.27 (m, 2H), 7.23 (s, 1H), 6.78 (s, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 3.29-3.23 (m, 2H), 3.03 (d, J = 11.3 Hz, 2H), 2.71-2.64 (m, 2H), 2.57 (q, J = 7.5 Hz, 4H), 2.38-2.25 (m, 5H), 2.15 (s, 3H), 1.85 (d, J = 11.7 Hz, 2H), 1.61-1.51 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0171] 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 [ka] 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 treated 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 tBu (0.07 g, 0.77 mmol) was added, and the mixture was heated to 80°C under nitrogen gas protection and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and then separated by column chromatography. The obtained crude product was further separated by a preparative column and N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (50.5 mg, yield: 21.3%) was obtained. MS m / z (ESI): 611.4 [M+H] + .

[0172] 1 HNMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.43 (d, J = 4.6 Hz, 2H), 8.26 (s, 1H), 7.98 (s, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.73 (d, J = 4.4 Hz, 1H), 7.46 (q, J = 6.9 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.26 (s, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 3.76 (s, 3H), 2.98 (d, J = 11.1 Hz, 2H), 2.71 (t, J = 11.6 Hz, 2H), 2.32 (s, 5H), 2.15 (s, 3H), 1.85 (d, J = 11.9 Hz, 2H), 1.64-1.50 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H).

[0173] 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 [ka] A solution of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.20 g, 0.55 mmol) in toluene (10 mL) was treated with 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) was added, and the mixture was heated to 80°C under nitrogen gas protection and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and then separated by column chromatography. The obtained crude product was further separated by a preparative column and N 4 -(5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (96.8 mg, yield: 28.8%) was obtained. MS m / z (ESI): 609.4 [M+H] + .

[0174] 1HNMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (tdd, J = 7.7, 5.1, 1.9 Hz, 1H), 7.36-7.26 (m, 2H), 6.78 (s, 1H), 6.71 (s, 1H), 5.83 (s, 1H), 3.75 (s, 3H), 2.67 (t, J = 11.2 Hz, 2H), 2.41-2.23 (m, 5H), 2.19-2.07 (m, 4H), 1.87 (d, J = 11.7 Hz, 2H), 1.67-1.54 (m, 2H), 0.97-0.87 (m, 2H), 0.63-0.54 (m, 2H).

[0175] Example 9:N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 Preparation of -(2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine [ka] A solution of 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.16 g, 0.39 mmol) in toluene (10 mL) was treated with 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 tBu (0.07 g, 0.78 mmol) was added, and the mixture was heated to 80°C under nitrogen gas protection and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and then separated by column chromatography. The obtained crude product was further separated by a preparative column and purified by N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N6-(2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (65 mg, yield: 25.2%) was obtained. MS m / z (ESI): 649.4 [M+H] + .

[0176] 1 HNMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.45-8.39 (m, 2H), 8.26 (d, J = 0.8 Hz, 1H), 8.06 (s, 1H), 7.99 (t, J = 1.9 Hz, 1H), 7.91 (td, J = 8.0, 1.9 Hz, 1H), 7.87 (s, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.36-7.25 (m, 2H), 6.80 (s, 1H), 5.93 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.12 (d, J = 11.1 Hz, 2H), 2.63-2.53 (m, 4H), 2.39-2.27 (m, 4H), 2.26-2.19 (m, 1H), 2.15 (s, 3H), 1.82 (d, J = 11.5 Hz, 2H), 1.61-1.48 (m, 2H).

[0177] Example 10:N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 Preparation of -(2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (100 mg, 0.33 mmol) and 2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinoaniline (106 mg, 0.37 mmol), NaO t Bu (64 mg, 0.67 mmol) and BrettPhos Pd-G3 (30 mg, 0.03 mmol) were added to toluene (15 mL) and heated to 90 °C under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated by a preparative column to obtain the crude product. 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine (40.5 mg, yield: 22.0%) was obtained. MS m / z (ESI): 553.2 [M+H] + .

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.46 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.27 (s,1H), 8.13 (s, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.75-7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.49-7.44 (m, 2H), 7.34-7.28 (m, 2H), 6.83 (s, 1H), 5.96 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.75-3.72 (m,4H), 2.87-2.83 (m, 4H).

[0179] Example 11: N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6Preparation of -(2-methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-4,6-diamine [ka] 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidin-4-amine (62 mg, 0.21 mmol) and 2-methoxy-5-(1-methyl-1H-pyridin-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 under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated by a preparative column to obtain the crude product. 4 -(2-(2-fluorophenyl)pyridin-4-yl)-N 6 -(2-Methoxy-5-(1-methyl-1H-pyridin-4-yl)-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-4,6-diamine (25.5 mg, yield: 21.9%) was obtained. MS m / z (ESI): 566.2 [M+H] + .

[0180] 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.47-8.40 (m, 2H), 8.27 (s, 1H), 8.06 (s, 1H), 7.99 (t, J = 2.0 Hz, 1H), 7.94-7.87 (m, 2H), 7.74-7.72 (dd, J = 5.7, 2.2 Hz, 1H), 7.50-7.42 (m, 2H), 7.33-7.28 (m, 2H), 6.81 (s, 1H), 5.94 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.88-2.84 (m, 4H), 2.48-2.41 (m, 4H), 2.24 (s, 3H).

[0181] 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 [ka]

[0182] First step: Synthesis of 5-(2-fluorophenyl)pyridin-3-amine [ka]

[0183] The procedure was carried out with reference to the first step of Example 1.

[0184] Second process: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 [ka] 4,6-Dichloropyrimidine (60 mg, 0.40 mmol), 5-(2-fluorophenyl)pyridin-3-amine (76 mg, 0.40 mmol), and 2-methoxy-5-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (130 mg, 0.40 mmol) were dissolved in anhydrous 1,4-dioxane (8 mL), and the solution was heated under nitrogen gas protection with BrettPhos Pd-G3 (37 mg, 0.04 mmol) and NaO. t Bu (77 mg, 0.81 mmol) was added, and the mixture was heated to 85° C. and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and then separated by column chromatography to obtain a crude product, which was then separated by a high-performance liquid chromatography column to obtain N 4 -(5-(2-fluorophenyl)pyridin-3-yl)-N 6 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-4,6-diamine (14 mg, yield: 6.1%) was obtained. MS m / z (ESI): 583.2 [M+H] + .

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.30-8.26 (m, 2H), 8.24 (s, 1H), 8.18 (s, 1H), 7.57 (td, J = 7.8, 1.8 Hz, 1H), 7.54-7.44 (m, 1H), 7.44-7.29 (m, 2H), 7.21 (s, 1H), 6.70 (s, 1H), 5.85 (s, 1H), 3.75 (s, 3H), 3.09 (d, J = 11.3 Hz, 2H), 2.63 (t, J = 11.4 Hz, 3H), 2.37-2.25 (m, 5H), 2.16 (s, 3H), 2.15 (s, 3H), 1.86 (d, J = 11.9 Hz, 2H), 1.67-1.47 (m, 2H).

[0186] Example 13: N4 -(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 [ka] 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), TFA (0.4 mL, 5.385 mmol) was added, and the mixture was heated to 130 °C in a sealed tube under N protection overnight. After cooling to room temperature, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography to obtain N. 4 -(5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4,6-diamine (35.0 mg, 0.060 mmol, yield: 19.3%) was obtained. MS m / z (ESI): 587.2 [M+H] + .

[0187] 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.55 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.92 (td, J = 7.9, 1.7 Hz, 1H), 7.74 (dd, J = 5.8, 2.1 Hz, 1H), 7.57 - 7.39 (m, 2H), 7.37 - 7.27 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.14 (s, 1H), 3.80 (s, 3H), 3.39 (d, J = 11.7 Hz, 2H), 2.68 (t, J = 11.5 Hz, 2H), 2.29 (dd, J = 13.7, 8.9 Hz, 5H), 2.14 (s, 3H), 1.85 (d, J = 12.3 Hz, 2H), 1.55 (dd, J = 13.1, 9.4 Hz, 2H).

[0188] 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 [ka]

[0189] Synthesized with reference to the preparation method of Example 13. MS m / z (ESI): 603.4 [M+H] + .

[0190] 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.92 (td. 1H), 3.83 (s, 3H), 2.73 - 2.62 (m, 2H), 2.37 - 2.24 (m, 5H), 2.14 (s, 3H), 1.86 (d, J = 12.1 Hz, 2H), 1.65 - 1.51 (m, 2H).

[0191] 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 [ka]

[0192] Synthesized according to the method of Example 3. MS m / z (ESI): 647.4 [M+H] + .

[0193] 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.63 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.96 - 7.86 (m, 2H), 7.75 (dd, J = 5.7, 2.1 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.36 - 7.28 (m, 2H), 6.83 (s, 1H), 6.12 (s, 1H), 3.83 (s, 3H), 3.28 (t, 2H), 2.94 (t, 2H), 2.71 - 2.64 (m, 2H), 2.32 (m, 5H), 2.15 (s, 3H), 2.00 (q, J = 7.0 Hz, 2H), 1.86 (d, J = 11.9 Hz, 2H), 1.59 (q, J = 11.0 Hz, 2H).

[0194] 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 [ka]

[0195] Synthesized according to the method of Example 3. MS m / z (ESI): 597.4 [M+H] + .

[0196] 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (tdd, J = 7.5, 5.1, 1.9 Hz, 1H), 7.42 - 7.27 (m, 2H), 7.20 (s, 1H), 6.72 (s, 1H), 5.90 (s, 1H), 3.76 (s, 3H), 3.10 (d, J = 11.3 Hz, 2H), 2.69 - 2.59 (m, 2H), 2.37 (brs, 4H), 2.29 (q, J = 7.4 Hz, 2H), 2.16 (s, 3H), 1.97 - 1.78 (m, 2H), 1.66 - 1.48 (m, 2H), 0.98 (t, J = 7.1 Hz, 3H).

[0197] 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 [ka]

[0198] Synthesized according to the method of Example 13. MS m / z (ESI): 607.4 [M+H] + .

[0199] 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.96 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.92 (td, J = 7.9, 1.9 Hz, 1H), 7.74 (dd, J = 5.7, 2.1 Hz, 1H), 7.69 (s, 1H), 7.47 (tdd, J = 7.3, 5.0, 1.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.23 (s, 1H), 6.07 (s, 1H), 2.71 - 2.61 (m, 2H), 2.37 - 2.25 (m, 4H), 2.14 (s, 3H), 1.90 - 1.82 (m, 2H), 1.57 (dd, J = 11.9, 3.6 Hz, 2H).

[0200] 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 [ka]

[0201] Synthesized with reference to the preparation method of Example 13. MS m / z (ESI): 587.4 [M+H] + .

[0202] 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.82 (s, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.91 (td, J = 7.9, 1.9 Hz, 1H), 7.73 (dd, J = 5.7, 2.1 Hz, 1H), 7.46 (ddd, J = 7.4, 5.2, 2.1 Hz, 1H), 7.37 - 7.23 (m, 3H), 7.08 (s, 1H), 5.87 (s, 1H), 3.10 (d, J = 11.3 Hz, 2H), 2.60 (t, J = 11.6 Hz, 2H), 2.30 (tt, J = 11.0, 3.4 Hz, 4H), 2.22 (s, 3H), 2.14 (s, 3H), 1.86 (d, J = 12.0 Hz, 2H), 1.56 (tt, J = 11.8, 5.9 Hz, 2H).

[0203] Biological Measurement and Evaluation (Cell proliferation experiment) (1) Reagents and consumables DMEM medium (Gibco, 11965118) RPMI1640 medium (Gibco, 11875119) Fetal bovine serum (FBS) (GBICO, Cat#10099-141) CellTiter-Glo® Luminescent Cell Activity Assay Reagent Kit (Promega, Cat# G7572) Black transparent flat-base 96-well plate (Corning®, Cat#3603)

[0204] (2) Equipment SpectraMax Multilabel Microwell Plate Detector MD, 2104-0010A, Carbon dioxide incubator, Thermo Scientific 3100 series, Biological Safety Cabinet, Thermo Scientific, 1300 Series A2, Inverted microscope, Olympus, CKX41SF, SIEMENS refrigerator, KK25E76TI.

[0205] (3) Cell lines and culture conditions [Table 1]

[0206] (4) Experimental process 1. Cell culture and inoculation: (1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected by trypan blue exclusion to ensure that cell viability was 90% or higher. (2) The cell concentration was adjusted to the required final density, and 90 μL of the cell suspension was added to a 96-well plate. (3) In a 96-well plate, the cells were incubated overnight at 37°C, 5% CO2 and 95% humidity.

[0207] 2. T0 reference data: (1) 10 μL of PBS was added to each well of the TO plate containing the cells. (2) The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature for 30 minutes. (3) The same volume of CTG solution was added to each well. (4) The cells were shaken for 5 minutes on a rail-mounted shaker to divide them. (5) The cell plate was left at room temperature for 20 minutes to allow the fluorescent signal to stabilize. (6) The TO fluorescence signal value was read.

[0208] 3. Compound Dilution and Addition (1) According to the compound information table, the corresponding volume of DMSO was added to the corresponding compound powder to prepare a 10 mM stock solution. (2) Compound solutions diluted 1000-fold and 3.16-fold were prepared. (3) The 1000x diluted compound solution was diluted 100-fold with PBS to prepare 10x compound solutions, with the highest concentration being 10 μM. Nine concentrations were diluted 3.16-fold, and 10 μL of the drug solution was added to each well of a 96-well plate to inoculate the cells. Three wells were prepared for each compound concentration, and the final DMSO concentration was 0.1%. (4) The cells were placed in a 96-well plate containing the drug and subsequently cultured at 37°C, 5% CO2 and 95% humidity for 72 hours, after which CTG analysis was performed.

[0209] 4. Reading the fluorescent signal (1) The CTG reagent was thawed and the cell plate was allowed to equilibrate to room temperature for 30 minutes. (2) The same volume of CTG solution was added to each well. (3) The cells were shaken for 5 minutes on a rail-mounted shaker to induce cell division. (4) The cell plate was left at room temperature for 20 minutes to allow the fluorescent signal to stabilize. (5) The fluorescence value was read.

[0210] 5. Data processing Data were analyzed with GraphPad Prism 7.0 software, and dose-effect curves were obtained by fitting the data with nonlinear S-curve regression, thereby determining IC 50 The values ​​(unit: nM) were calculated, and specific experimental results are shown in Table 1.

[0211] Cell viability (%) = (Lum test drug - Lum medium control) / (Lum cell control - Lum medium control) x 100%.

[0212] [Table 2]

[0213] According to the biological activity data of the compounds in the specific examples, the series of compounds according to the present invention have strong inhibitory effects against 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 against EGFR WT.

[0214] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. It should also be understood that, after reading the above disclosure of the present invention, one skilled in the art may make various variations and modifications to the present invention, and that equivalents thereof are also encompassed within the scope of the claims of the present invention. Furthermore, the present invention includes the following aspects. [Aspect 1] Formula (I): [ka] (In the formula: X 1 and X 2 are each independently N or CR 7 and Z is N or CH; R 1 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, hydroxy group, C 1-10 Alkoxy group, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic oxy group, C 6-10 Aryloxy group, 5-10 membered heteroaryloxy group, -SF 5 , -S(O) r R 8 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 and -C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: R 2 is hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-8 Alkyl-C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: R 3 and R 4 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 cycloalkyl groups and 3- to 12-membered heterocyclic groups, or R 3 and R 4 together with the nitrogen atom to which they are directly attached form a 4-12 membered heterocyclic group, which may optionally further contain deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: Each R5 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 or, when m≧2, two adjacent R 5 are one C together with the parts directly connected to them. 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups, C 6-10 forming an aryl group or a 5-10 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: R 6 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: Each R 7 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C0-8 Alkyl-OC(O)R 10 、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 or two R 7 are one C together with the parts directly connected to them. 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups, C 6-10 forming an aryl group or a 5-10 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, ═O, -C 0-8 Alkyl-SF 5 、-C 0-8 Alkyl-S(O) r R 8 、-C 0-8 Alkyl-OR 9 、-C 0-8 Alkyl-C(O)OR 9 、-C 0-8 Alkyl-C(O)R 10 、-C 0-8 Alkyl-OC(O)R 10、-C 0-8 Alkyl-NR 11 R 12 、-C 0-8 Alkyl-C(=NR 11 )R 10 、-C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: Each R 8 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: Each R 9 are independently hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 aryl groups and 5-10 membered heteroaryl groups, said groups independently optionally further containing deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-10 Alkyl group, C1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: Each R 10 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: Each R 11 and R 12 are independently hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl group, 5-10 membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 alkanoyl groups, which groups may independently optionally further comprise deuterium, halogen, hydroxyl groups, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; Alternatively, R 11 and R 12 together with the nitrogen atom directly linked thereto form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group may optionally further contain deuterium, halogen, hydroxyl group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 optionally substituted by one or more substituents selected from the group consisting of alkanoyl groups; m is 0, 1, 2, 3, 4, or 5, and each r is independently 0, 1, or 2; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. [Aspect 2] X 1 and X 2 are each independently N or CR 7 and R 1 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, hydroxy group, C 1-4 Alkoxy group, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic oxy group, C 6-8 Aryloxy group, 5-8 membered heteroaryloxy group, -SF 5 , -S(O) r R 8 , -C(O)OR 9 , -C(O)R 10 and -OC(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, hydroxyl group, ═O, cyano group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl group, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 11 R 12 and optionally substituted with one or more substituents selected from the group consisting of: R 2 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: R 3 and R 4 are independently hydrogen, deuterium, hydroxyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclic groups, or R 3 and R 4 together with the nitrogen atom to which they are directly attached form a 4-12 membered monocyclic or polycyclic heterocyclic group, which may optionally further contain deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano group, nitro group, azido group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: Each R 5 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 or, when m≧2, two adjacent R 5 are one C together with the parts directly connected to them. 5-8 Cycloalkyl groups, 5-8 membered heterocyclic groups, C 6-8 forming an aryl group or a 5-8 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azido, C1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: R 6 represents hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 wherein said groups are independently optionally further selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: Each R 7 are independently hydrogen, deuterium, halogen, cyano group, nitro group, azide group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 or two R 7 are one C together with the parts directly connected to them. 5-8 Cycloalkyl groups, 5-8 membered heterocyclic groups, C 6-8 forming an aryl group or a 5-8 membered heteroaryl group, said groups independently optionally further comprising deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl group, halogen-substituted C 1-4 Alkyl group, deuterium-substituted C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-8 Aryl group, 5-8 membered heteroaryl group, ═O, -C 0-4 Alkyl-SF 5 、-C 0-4 Alkyl-S(O) r R 8 、-C 0-4 Alkyl-OR 9 、-C 0-4 Alkyl-C(O)OR 9 、-C 0-4 Alkyl-C(O)R 10 、-C 0-4 Alkyl-OC(O)R 10 、-C 0-4 Alkyl-NR 11 R 12 、-C 0-4 Alkyl-C(=NR 11 )R 10 、-C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 、-C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 and optionally substituted with one or more substituents selected from the group consisting of: where R 8 、R 9 、R 10 、R 11 、R 12 2. A compound of formula (I) according to embodiment 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that m and r are as defined in embodiment 1. [Aspect 3] Formula (I) or Formula (II):

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Claims

1. Formula (III): 【Chemistry 1】 (In the formula: X 1 and X 2 are each independently N or CH; Y is a bond, O, N (R 14 ) or C(R 15 R 16 ) and R 1 is selected from halogen, methoxy, ethoxy, and isopropoxy, which may independently and optionally be further substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and bromine; R 2 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl groups, which groups are independently and optionally further substituted by one or more substituents selected from methyl and ethyl groups; R 5a is selected from hydrogen, fluorine, chlorine and bromine; R 5e is selected from hydrogen, fluorine, chlorine and bromine; R 14 is selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group; R 15 and R 16 are each independently selected from hydrogen and a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group optionally further comprises C 1-4 and optionally substituted with one or more substituents selected from alkyl groups. A compound represented by the formula:

2. R 2 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, and said groups may independently and optionally be further substituted by one or more substituents selected from methyl and ethyl.

3. R 1 is selected from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, and isopropoxy groups, which may be independently and optionally further substituted by one or more substituents selected from fluorine, chlorine, and bromine; R 5a is hydrogen, R 5e is selected from hydrogen, fluorine, chlorine and bromine; 2. A compound represented by formula (III) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. R 14 is selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group; R 15 and R 16 are each independently selected from the group consisting of hydrogen, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, and may optionally be further substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl. The compound represented by formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 . 【Request Item 5】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 2. The compound represented by formula (III) according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

6. The following steps: 【Transformation 7】 (where X is chlorine or bromine, and X 1 , X 2 , Y, R 1 , R 2 , R 5a and R 5e are as defined in claim 1) 2. A method for producing the compound represented by formula (III) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising:

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

8. 8. The pharmaceutical composition of claim 7 for treating and / or preventing cancer, tumor or metastatic disease, at least in part associated with the EGFR Del19 mutation, the EGFR L858R mutation, the EGFR L858R / C797S double mutation or the EGFR Del19 / C797S double mutation.

9. 8. The pharmaceutical composition of claim 7 for preventing and / or treating tumors, cancers and / or metastatic diseases caused by hyperproliferation and cell death-inducing disorders.

10. 8. The pharmaceutical composition according to claim 7, for preventing and / or treating lung cancer, pancreatic cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urinary tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma, at least some of which are associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation or EGFR Del19 / C797S double mutation.

11. The pharmaceutical composition described in claim 10, wherein the lung cancer is non-small cell lung cancer; the head and neck tumor is head and neck cancer; the breast and other gynecological tumor is breast cancer, ovarian cancer or uterine cancer; and the gastrointestinal tumor is colon cancer or gastric cancer.

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