Pyrimidine-4,6-diamine derivatives, methods for preparing the same, and pharmaceutical applications

Abstract

The present invention relates to pyrimidine-4,6-diamine derivatives, methods for preparing the same, and pharmaceutical applications. In particular, the present invention relates to pyrimidine-4,6-diamine derivatives having the structure of formula (I), methods for preparing the same, drug compositions containing the same, and the use of the same as EGFR inhibitors and the use of the same in the manufacture of drugs for treating and / or preventing cancer, tumors, or metastatic diseases at least partially associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, and in particular to the use in the manufacture of drugs for treating hyperproliferative diseases and diseases in which apoptosis disorders are induced. Herein, each substituent of formula (I) is as defined in the specification.

Description

Technology Field

[0001] The present invention belongs to the field of drug synthesis, and specifically relates to a pyrimidine-4,6-diamine derivative, a method for manufacturing the same, and pharmaceutical applications. Background Technology

[0002] Lung cancer is the malignant tumor with the highest mortality rate worldwide, posing a serious threat to human health, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancers (Bray, F. etc. 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, molecular mechanisms such as various gene mutations and expression abnormalities have been proven to be associated with the onset of NSCLC, among which EGFR is a major driver gene. The frequency of EGFR activating mutations among NSCLC patients worldwide is approximately 17% (Hirsch, FR etc. Lung cancer: current therapies and new targeted treatments. Lancet 389 , 299-311, 2017), the East Asian group is relatively sensitive, with a mutation frequency of about 50% (Passaro, A., Jδnne, PA, Mok, T. . Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2, 377-391, 2021). EGFR activating mutations occur mainly in exons 18–21, and deletion mutations in exon 19 (Del19) and point mutations in L858R of exon 21 are the most common mutant subtypes, accounting for more than 80% of all mutant types (Passaro, A. etc. Recent Advances on the Role of EGFR Tyrosine Kinase Inhibitors in the Management of NSCLC With Uncommon, Non Exon 20 Insertions, EGFR Mutations. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 16 (, 764-773, 2021). These mutations can lead to ligand-independent receptor activation and promote the survival and proliferation of tumor cells. First and second-generation EGFR tyrosine kinase inhibitors (TKIs) target precisely these two active mutations. Compared to platinum-based chemotherapy, first and second-generation EGFR TKIs can significantly extend progression-free survival (Rosell, R. etc. 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, L.V. etc.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), 단 약물 사용 10-12개월 후에는 종종 약물 내성이 나타날 수 있다(Mitsudomi, T. etc. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The Lancet. Oncology 11 , 121-128, 2010); (Park, K. etc. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. The Lancet. Oncology 17(, 577-589, 2016). The EGFR T790M mutation is a major mechanism of drug resistance to first and second-generation EGFR TKIs, and subsequently, the third-generation EGFR TKI, osimertinib, was developed to selectively inhibit EGFR T790M and common EGFR mutations. In the results of the Phase 3 FLAURA clinical trial, osimertinib demonstrated significantly superior therapeutic efficacy compared to first-generation EGFR TKIs and was shown to significantly improve progression-free survival (18.9 vs. 10.2 months) and total survival (38.6 vs. 31.8 months) (Soria, JC etc. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine 378 (, 113-125, 2018), this served as a direct catalyst for placing osimertinib in the ranks of first-line treatment options.

[0003] Despite the remarkable therapeutic efficacy of osimertinib, drug resistance inevitably develops and leads to disease progression. Several EGFR-dependent (on-target) and non-dependent (off-target) drug resistance mechanisms have been reported in both preclinical and clinical studies (Passaro, A., Jδnne, PA, Mok, T. etc. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer 2 , 377-391, 2021). According to an analysis of the Phase 3 clinical trial FLAURA, EGFR-dependent drug resistance developed in approximately 10–15% of patients receiving osimertinib as a first-line treatment for end-stage NSCLC, among which C797S on exon 20 was the most significant non-EGFR mutation, accounting for 7% (Ramalingam, SS etc.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 causes drug resistance by preventing osimertinib from forming a covalent bond within the ATP binding domain of EGFR. Furthermore, there is no evidence indicating that gain-of-function mutations in EGFR T790M may occur in patients treated with osimertinib as a first-line therapy (Ramalingam, SS etc. 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 is likely one of the important mechanisms of first-line drug resistance treatment with osimertinib (Tumbrink, HL, Heimsoeth, A. & Sos, ML The next tier of EGFR resistance mutations in lung cancer. Oncogene 40 Next-generation EGFR TKIs with high activity and selectivity for the double mutation consisting of Del19 / L858R and C797S can meet the clinical needs of some of these patients as a next-generation treatment option following first-line drug resistance treatment with osimertinib.

[0004] The object of the present invention is to provide pyrimidine-4,6-diamine derivatives, methods for preparing the same, and pharmaceutical applications. The series of compounds of the present invention have a very potent inhibitory effect on the cytological activity of EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, and have high selectivity for EGFR wild-type. Therefore, they can be widely used in the manufacture of drugs to treat and / or prevent cancer, tumors, or metastatic diseases at least partially associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, and in particular, can be widely used in the manufacture of drugs to treat hyperproliferative diseases and diseases induced by apoptosis disorders, thus developing next-generation EGFR inhibitors.

[0005] In a first aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] ,

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

[0008] Z is N or CH;

[0009] R1 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10-membered heteroaryl, hydroxy, C 1-10 Alkoxy, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyloxy, C 6-10 Aryloxy, 5-10 prismatic heteroaryloxy, -SF5, S(O) r R 8,-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 Selected from, said atomic group is independently deuterium, halogen, hydroxy, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0010] R2 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prismatic heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-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(R11 )-C(=NR 12 )R 10 and -C 0-8 Alkyl-C(O)NR 11 R 12 Selected from, wherein the atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0011] R3 and R4 are each independently hydrogen, deuterium, hydroxyl, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12Selected from cycloalkyl and 3-12-membered heterocyclils, or, R3 and R4 form 4-12-membered heterocyclils with nitrogen atoms directly connected thereto, said atomic groups are deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 The atomic group is optionally additionally substituted by one or more substituents selected from, wherein the atomic group is deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8Alkyl-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 It is further additionally substituted by one or more optionally selected substituents from;

[0012] Each R5 is independently hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prismatic heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-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(=NR12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Selected from, or if m≥2, C with two adjacent R5s among them, together with the parts directly connected to them. 5-10 Cycloalkyl, 5-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, wherein the atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0013] R6 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prismatic heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-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 Selected from, said atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0014] Each R7 is independently hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prismatic heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-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 12and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Selected from, or the two R7s are C together with the part directly connected to them. 5-10 Cycloalkyl, 5-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, wherein the atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0015] Each R8 is independently hydrogen, deuterium, hydroxyl, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 syndrome heteroaryls and -NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, hydroxy, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0016] Each R9 is independently hydrogen, deuterium, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Selected from aryls and 5-10-membered heteroaryls, said atomic group is independently deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0017] Each R 10 Silver contains hydrogen, deuterium, hydroxyl, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, C 3-12Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy and -NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0018] Each R 11 and R 12 Each independently consists of hydrogen, deuterium, hydroxyl, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkinyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Selected from alkanoyls, wherein the atomic group is independently deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Optionally additionally substituted by one or more substituents selected from the alkanoyle,

[0019] Or, R 11 and R 12 It forms a 4-10-membered heterocyclyl or a 5-10-membered heteroaryl with a nitrogen atom directly connected to them, and the 4-10-membered heterocyclyl or 5-10-membered heteroaryl is deuterium, halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 Aril, C 6-10 Aryloxy, 5-10 won heteroaryl, 5-10 won heteroaryloxy, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Optionally additionally substituted by one or more substituents selected from the alkanoyle;

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

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

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

[0023] R1 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, hydroxy, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyloxy, C 6-8 Aryloxy, 5-8-membered heteroaryloxy, -SF5, S(O) r R8, -C(O)OR9, -C(O)R 10 and -OC(O)R 10 Selected from, wherein the atomic group is independently deuterium, halogen, hydroxy, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0024] R2 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10, -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 and -C 0-4 Alkyl-C(O)NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0025] R3 and R4 are each independently hydrogen, deuterium, hydroxyl, and C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Selected from cycloalkyl and 3-6-membered heterocyclils, or, R3 and R4 form 4-12-membered monocyclic heterocyclils or polycyclic heterocyclils with nitrogen atoms directly connected thereto, said atomic group is deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 The atomic group is optionally additionally substituted by one or more substituents selected from, wherein the atomic group is deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 It is further additionally substituted by one or more optionally selected substituents from;

[0026] Each R5 is independently hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R12 , -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 Selected from, or, if m≥2, one C with two adjacent R5s among them, together with a portion directly connected to them. 5-8 Cycloalkyl, 5-8-membered heterocyclyl, C 6-8 Forming an aryl or 5-8-membered heteroaryl, said atomic group independently deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

[0027] R6 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10 Selected from, said atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4Alkyl-SF5, -C 0-4 Alkyl-S(O) r R 8, -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 Optionally additionally substituted by one or more substituents selected from;

[0028] Each R7 is independently hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -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 Selected from, or, one C with a part where two R7s are directly connected to them. 5-8 Cycloalkyl, 5-8-membered heterocyclyl, C 6-8 Forming an aryl or 5-8-membered heteroaryl, wherein the atomic groups are independently deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =O, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O) r R8, -C 0-4 Alkyl-O-R9, -C 0-4 Alkyl-C(O)OR9, -C 0-4 Alkyl-C(O)R 10 , -C 0-4 Alkyl-OC(O)R 10 , -C 0-4 Alkyl-NR 11 R 12 , -C 0-4 Alkyl-C (=NR) 11 )R 10 , -C 0-4 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 Alkyl-C(O)NR 11 R 12 and -C 0-4 Alkyl-N(R 11 )-C(O)R 10Optionally additionally substituted by one or more substituents selected from;

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

[0030] As a preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (II):

[0031] ,

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

[0033] Z is N or CH;

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

[0035] R1 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, hydroxy, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyloxy, C 6-8 Selected from aryloxy and 5-8-membered heteroaryloxy, said atomic group is independently deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11R 12 Optionally additionally substituted by one or more substituents selected from;

[0036] R2 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -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 and -C(O)NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =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 10Optionally additionally substituted by one or more substituents selected from;

[0037] R 5a , R 5b , R 5c , R 5d and R 5e Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -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;

[0038] R6 is hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -SF5, -S(O) r R8, -O-R9, -C(O)OR9, -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR11 )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;

[0039] Each R7 is independently hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -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;

[0040] R 13a , R 13b , R 13c and R 13d Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -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 Selected from, or R 13a , R 13b , R 13c and R 13d C(O), C along with carbon atoms directly connected to them 3-6 Forming a cycloalkyl or 3-6 member heterocyclyl;

[0041] R 14 is hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, -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;

[0042] R 15 and R16 Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, -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, or, R 15 and R 16 C(O), C along with carbon atoms directly connected to them 3-6 Forming a cycloalkyl or 3-6-membered heterocyclyl, wherein the atomic group is deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =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 11R 12 and -N(R 11 )-C(O)R 10 Optionally additionally substituted by one or more substituents selected from;

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

[0044] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R2 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Selected from aryl, 5-8-membered heteroaryl, and -SF5, said atomic group is independently deuterium, halogen, cyano, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =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 Optionally additionally substituted by one or more substituents selected from;

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

[0046] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, each R1 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, allyl, vinyl, acetylene, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, hydroxy, C 1-4 Alkoxy, C 3-6 The atomic group is selected from cycloalkoxy and 3-6-membered heterocyclyloxy, wherein the atomic group is independently deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0047] R 5a , R 5b , R 5c , R 5d and R 5e Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Selected from cycloalkyl and 3-6-membered heterocyclyl;

[0048] R6 is hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen-substituted C 1-4Alkyl and deuterium-substituted C 1-4 Selected from alkyls;

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

[0050] Here, R 11 and R 12 is as described in the compound of formula (I) above.

[0051] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 13a , R 13b , R 13c and R 13d Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl and C 2-4 Selected from alkynyl, or, R 13a , R 13b , R 13c and R 13d C(O), C along with carbon atoms directly connected to them 3-6 Forming a cycloalkyl or 3-6 member heterocyclyl;

[0052] R 14 is hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, -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;

[0053] R 15 and R 16 Each independently consists of hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Selected from cycloalkyl, 3-6-membered heterocyclyl, or, R 15 and R 16 C(O), C along with carbon atoms directly connected to them 3-6 It forms a cycloalkyl or 3-6-membered heterocyclyl, wherein the atomic group is deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, =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 Optionally additionally substituted by one or more substituents selected from;

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

[0055] As a preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, the compound of formula (I) is a compound of the following formula (III):

[0056] ,

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

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

[0059] R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, isopropyl, allyl, vinyl, acetylene, cyclopropyl, cyclobutyl, morpholino, 3-6-membered oxacyclyl, 3-6-membered azacyclyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and 3-6-membered heterocyclyloxy, and the atomic group is independently selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, amino, mono-C 1-4 Alkylamino and di-C 1-4 Optionally further substituted by one or more substituents selected from alkylaminos;

[0060] R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azacyclobutyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and the atomic group is independently deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Optionally further substituted by one or more substituents selected from cycloalkyl and 3-6-membered heterocyclyl;

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

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

[0063] R 14 is hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, -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;

[0064] R 15 and R 16 Each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Selected from cycloalkyl, 3-6-membered heterocyclyl, or, R 15 and R 16 C(O), C along with carbon atoms directly connected to them 3-6 It forms a cycloalkyl or 3-6-membered heterocyclyl, wherein the atomic group is deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Optionally further substituted by one or more substituents selected from cycloalkyl, 3-6-membered heterocyclyl and =O;

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

[0066] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, each R8 is independently hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Aryl, 5-8-membered heteroaryl, and -NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, hydroxy, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0067] Each R9 is independently hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8 Selected from aryls and 5-8-membered heteroaryls, said atomic group is independently deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0068] Each R 10 Silver contains hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Selected from, said atomic group is independently deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 Optionally additionally substituted by one or more substituents selected from;

[0069] Each R 11 and R 12 Each independently consists of hydrogen, deuterium, hydroxyl, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-8Aryl, 5-8-membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Selected from alkanoyls, wherein the atomic group is independently deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Optionally additionally substituted by one or more substituents selected from the alkanoyle,

[0070] Or, R 11 and R 12 It forms a 4-8-membered heterocyclyl or a 5-8-membered heteroaryl with a nitrogen atom directly connected to them, and the 4-8-membered heterocyclyl or 5-8-membered heteroaryl is deuterium, halogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6-membered heterocyclyl, 3-6-membered heterocyclyloxy, C 6-8 Aril, C 6-8 Aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 It is optionally additionally substituted by one or more substituents selected from the alkanoyles.

[0071] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azacyclobutyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and the atomic group is independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, and diduteriomethyl.

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

[0073] R 5a is hydrogen;

[0074] R 5e It is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyanomethyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, and dedeuteriomethyl.

[0075] As a more preferred method, in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt, R 14 It is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, diduteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, and azacyclobutyl.

[0076] R 15 and R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, piperidinyl, morpholino, and piperazinyl, or, R 15 and R 16 The group forms C(O), cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, or azacyclobutyl together with a carbon atom directly connected to it, and the atomic group is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, diduteriomethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, azacyclobutyl, and =O.

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

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] or .

[0088] A second aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0089]

[0090] Here, X is chlorine or bromine, and X1, X2, Z, R1, R2, R3, R4, R5, R6 and m are as described in the compounds of formula (I).

[0091] 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 usable carrier.

[0092] The present invention also relates to the use of the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt in the manufacture of a drug for treating and / or preventing cancer, tumor, or metastatic disease at least partially associated with an EGFR Del19 mutation, an EGFR L858R mutation, an EGFR L858R / C797S double mutation, or an EGFR Del19 / C797S double mutation.

[0093] The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing and / or treating tumors, cancers, and / or metastatic diseases caused by hyperplasia and apoptosis-induced disorders. The present invention also relates to the use of a compound of formula (I) described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a drug 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 tumors, urological tumors, skin tumors, sarcoma, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma.

[0094] The present invention also relates to a compound of formula (I) that acts on a drug, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0095] The present invention also relates to the use of the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof for treating and / or preventing cancer, tumor, or metastatic disease at least partially associated with an EGFR Del19 mutation, an EGFR L858R mutation, an EGFR L858R / C797S double mutation, or an EGFR Del19 / C797S double mutation.

[0096] The present invention also relates to the use of the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof for preventing and / or treating tumors, cancers, and / or metastatic diseases caused by hyperplasia and apoptosis-induced disorders.

[0097] The present invention also relates to the use of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof for treating and / or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urological tumor, skin tumor, sarcoma, nasal and sinus inverted papilloma or nasal and sinus inverted papilloma-associated nasal and sinus squamous cell carcinoma.

[0098] The present invention also relates to a method for treating and / or preventing cancer, tumor, or metastatic disease at least partially associated with an EGFR Del19 mutation, an EGFR L858R mutation, an EGFR L858R / C797S double mutation, or an EGFR Del19 / C797S double mutation, comprising the step of administering a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a patient requiring treatment.

[0099] The present invention also relates to a method for preventing and / or treating tumors, cancers, and / or metastatic diseases caused by hyperproliferation and cell death induction disorders, comprising the step of administering a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a patient requiring treatment.

[0100] The present invention also relates to a method for treating and / or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumor, urological tumor, skin tumor, sarcoma, nasal and sinus inverted papilloma or nasal and sinus squamous cell carcinoma associated with nasal and sinus inverted papilloma, comprising the step of administering a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a patient requiring treatment. Specific details for implementing the invention

[0101] The inventor of the present application, through extensive and in-depth research, has for the first time developed a pyrimidine-4,6-diamine derivative having a structure as shown in Formula (I) below. The series of compounds of the present invention can be widely applied in the manufacture of drugs for treating and / or preventing cancer, tumors, or metastatic diseases at least partially associated with EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations, particularly drugs for treating hyperproliferative diseases and diseases in which apoptosis is induced, and are expected to be developed as next-generation EGFR inhibitors. Based on this, the present invention was completed.

[0102] Detailed Description: Unless otherwise explained or specifically explained, the terms used in this specification and claims have the following meanings.

[0103] "Alkyl" refers to a saturated aliphatic hydrocarbon group containing a straight or branched chain, preferably a straight-chain alkyl and a branched-chain alkyl comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, and is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, Includes, but is not limited to, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched-chain isomers thereof. "C 1-10 "alkyl" refers to straight-chain alkyls containing 1 to 10 carbon atoms and alkyls containing branched chains, and "C 1-4 "alkyl" refers to straight-chain alkyls and branched-chain alkyls containing 1 to 4 carbon atoms, and "C 0-8 "alkyl" refers to straight-chain alkyls containing 0 to 8 carbon atoms and alkyls containing branched chains, and "C 0-4 "Alkyl" refers to straight-chain alkyls containing 0 to 4 carbon atoms and branched-chain alkyls.

[0104] The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0105] "Cycloalkyl" or "carbon ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon may contain one or more (preferably 1, 2, or 3) double bonds in the cyclic hydrocarbon, but no ring has a completely conjugated π-electron system, and cycloalkyl is classified into monocyclic cycloalkyl and polycyclic cycloalkyl, preferably a cycloalkyl comprising 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl containing 3 to 12 carbon atoms, and "C 3-6 "Cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, and "C 5-10 "Cycloalkyl" refers to a cycloalkyl containing 5 to 10 carbon atoms, and "C 5-8 "Cycloalkyl" refers to a cycloalkyl containing 5 to 8 carbon atoms, wherein:

[0106] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0107] Polycyclic cycloalkyls include spiro, condensed, and bridged cycloalkyls. "Spirocycloalkyl" refers to a polycyclic group in which one carbon atom (referred to as a spiro atom) is shared between monocyclic groups, and the rings may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between rings, spirocycloalkyls are classified as monospirocycloalkyls, bispirocycloalkyls, or polyspirocycloalkyls, and spirocycloalkyls include, but are not limited to, the following:

[0108] .

[0109] "Condensed cycloalkyl" refers to a polycyclic group composed solely of carbon, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring in the system, wherein one or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of rings formed, condensed cycloalkyls may be classified as noncyclic, tricyclic, tetracyclic, or polycyclic, and condensed cycloalkyls include, but are not limited to, the following:

[0110] .

[0111] "Bridged cycloalkyl" refers to a polycyclic group consisting solely of carbon atoms sharing two carbon atoms that are not directly connected in any two rings, and such rings may contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated π-electron system. Depending on the number of rings formed, they may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyls, and bridged cycloalkyls include, but are not limited to, the following:

[0112] .

[0113] The above cycloalkyl ring may be condensed into an aryl, heteroaryl, or heterocycloaryl ring, wherein the ring connected together with the parent structure is a cycloalkyl, and includes but is not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0114] The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0115] "Heterocyclil" or "hetero-ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon may contain one or more (preferably 1, 2 to 3) double bonds in the cyclic hydrocarbon, but no ring has a completely conjugated π-electron system, and one or more (preferably 1, 2, 3 to 4) ring atoms of the heterocyclil are nitrogen, oxygen, S(O)(=NH) or S(O) r A heteroatom selected from (where r is an integer 0, 1, or 2), provided that it does not include a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, preferably a heterocyclil comprising 3 to 12 or 3 to 8 or 3 to 6 or 5 to 6 ring atoms, for example, "3-6-membered heterocyclil" refers to a ring group comprising 3 to 6 ring atoms, "3-12-membered heterocyclil" refers to a ring group comprising 3 to 12 ring atoms, "4-8-membered heterocyclil" refers to a ring group comprising 4 to 8 ring atoms, "4-10-membered heterocyclil" refers to a ring group comprising 4 to 10 ring atoms, "4-12-membered heterocyclil" refers to a ring group comprising 4 to 12 ring atoms, and "5-6-membered "Heterocyclil" refers to a ring group containing 5 to 6 ring atoms, "5-8-membered heterocyclil" refers to a ring group containing 5 to 8 ring atoms, and "5-10-membered heterocyclil" refers to a ring group containing 5 to 10 ring atoms.

[0116] Monocyclic heterocyclils include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomomorpholinyl, homopiperazinyl, etc.

[0117] Polycyclic heterocyclils include spiro, condensed, and bridged heterocyclils. "Spiro heterocyclil" refers to a polycyclic heterocyclil group in which one atom (referred to as a spiro atom) is shared between monocyclic atoms, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (Here, r is a heteroatom selected from the integers 0, 1, and 2), and the remaining ring atoms are carbons. They may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the ring and the ring, spiroheterocyclils are classified as monospiroheterocyclils, bispiroheterocyclils, or polyspiroheterocyclils. Spiroheterocyclils include, but are not limited to, the following:

[0118] .

[0119] "Condensed heterocyclil" refers to a polycyclic heterocyclil in which each ring in the system shares a pair of atoms adjacent to another ring in the system, wherein one or more (preferably 1, 2, 3, or 4) rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π-electron system, and wherein one or more (preferably 1, 2, 3, or 4) ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (Here, r is a heteroatom selected from integers 0, 1, and 2), and the remaining ring atoms are carbons. Depending on the number of rings formed, they may be classified into cyclic, tricyclic, tetracyclic, or polycyclic condensed heterocycloalkyls, and condensed heterocycloalkyls include, but are not limited to, the following:

[0120] .

[0121] "Bridged heterocyclil" refers to a polycyclic heterocyclil in which any two rings share two atoms that are not directly connected, wherein the rings may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings have a completely conjugated π-electron system, and wherein one or more (preferably 1, 2, 3, or 4) ring atoms are nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer 0, 1, or 2) a heteroatom is selected from the integers 0, 1, or 2, and the remaining ring atoms are carbons. Depending on the number of formed rings, they may be classified as cyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclils, and bridged heterocyclils include, but are not limited to, the following:

[0122]

[0123] .

[0124] The above heterocyclyl ring may be condensed to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected together with the parent structure is heterocyclyl, and includes, but is not limited to, the following:

[0125] .

[0126] The heterocyclyl may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-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 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0127] "Aryl" or "aromatic ring" refers to a monocyclic or condensed polycyclic (i.e., a ring sharing an adjacent pair of carbon atoms) atomic group composed solely of carbon, specifically a polycyclic (i.e., a ring having an adjacent pair of carbon atoms) atomic group having a conjugated π-electron system, preferably an aryl composed solely of carbon comprising 6 to 10 or 6 to 8 or 6 carbons, for example, "C 6-10 "Aryl" refers to an aryl composed solely of carbons containing 6 to 10 carbons, and "C 6-8 "Aryl" refers to an aryl composed solely of carbons containing 6 to 8 carbons, and includes, but is not limited to, phenyl and naphthyl. The aryl ring may be condensed to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected together with the parent structure is an aryl ring, and includes, but is not limited to, the following:

[0128] .

[0129] "Aryl" may be substituted or unsubstituted, and in the case of substitution, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0130] "Heteroaryl" refers to a heteroaromatic system comprising one or more (preferably 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms comprise nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, or 2), and preferably a heteroaromatic system comprising 5 to 10 or 5 to 8 or 5 to 6 ring atoms, for example, "5-8-membered heteroaryl" refers to a heteroaromatic system comprising 5 to 8 ring atoms, and "5-10-membered heteroaryl" refers to a heteroaromatic system comprising 5 to 10 ring atoms, and includes but is not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The above heteroaryl ring may be condensed to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected together with the parent structure is a heteroaryl ring, and comprises, but is not limited to, the following:

[0131] .

[0132] "Heteroaryl" may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10, -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0133] "Alkenyl" refers to an alkyl group as defined above, comprising at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl containing a straight or branched chain having 2 to 10 or 2 to 4 carbons, for example, "C 2-10 "Alkenyl" refers to an alkenyl containing a straight chain or a branched chain containing 2 to 10 carbons, and "C 2-4 "Alkenyl" refers to an alkenyl containing a straight chain or a branched chain containing 2 to 4 carbons. It includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl.

[0134] "Alkenyl" may be substituted or unsubstituted, and in the case of substitution, the substituents are preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8Alkyl-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 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0135] "Alkynyl" refers to an alkyl group as defined above, comprising at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl containing a straight or branched chain having 2 to 10 or 2 to 4 carbons, for example, "C 2-10 "Alkynyl" refers to an alkenyl containing a straight chain or a branched chain containing 2 to 10 carbons, and "C 2-4 "Alkynyl" refers to an alkynyl containing a straight chain or a branched chain containing 2 to 4 carbons. It includes, but is not limited to, ethinyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0136] "Alkynyl" may be substituted or unsubstituted, and if substituted, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0137] "Alkoxy" refers to -O-alkyl, where the definition of alkyl is as stated above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy containing 1 to 10 carbons, and "C 1-4 "Alkoxy" includes alkyloxy containing 1 to 4 carbons, and includes but is not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0138] "Alkoxy" may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0139] "Cycloalkoxy" refers to -O-cycloalkyl, where the definition of cycloalkyl is as stated above, for example, "C 3-12 "Cycloalkoxy" refers to a cycloalkyloxy containing 3 to 12 carbons, and "C 3-8"Cycloalkoxy" refers to a cycloalkyloxy containing 3 to 8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.

[0140] "Cycloalkoxy" may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0141] "Heterocyclyloxy" refers to -O-heterocyclyl, where the definition of heterocyclyl is as described above, and heterocyclyloxy includes, but is not limited to, azacyclobutyloxy, oxyheterocyclylbutoxy, azacyclopentyloxy, nitrogen, oxyheterocyclylhexyloxy, etc.

[0142] "Heterocyclyloxy" may be substituted or unsubstituted, and if substituted, the substituents are preferably independently deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, =O, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O) r R8, -C 0-8 Alkyl-O-R9, -C 0-8 Alkyl-C(O)OR9, -C 0-8 Alkyl-C(O)R 10 , -C 0-8 Alkyl-OC(O)R 10 , -C 0-8 Alkyl-NR 11 R 12 , -C 0-8 Alkyl-C (=NR) 11 )R 10 , -C 0-8 Alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 Alkyl-C(O)NR 11 R 12 and -C 0-8 Alkyl-N(R 11 )-C(O)R 10 It is substituted by substituents that are one or more (preferably 1, 2, 3, or 4) atomic groups selected from.

[0143] "C1-10 "Alkanoyle" is C 1-10 It refers to the monovalent atomic group remaining after removing a hydroxyl group from an alkyl acid, and is generally "C 0-9 It is also indicated as "alkyl-C(O)-", for example, "C1alkyl-C(O)-" refers to acetyl, "C2alkyl-C(O)-" refers to propionyl, and "C3alkyl-C(O)-" refers to butyryl or isobutyryl.

[0144] "C 1-4 " is "C 1-4 Refers to "alkyl", and "C 0-4 " is "C 0-4 Refers to "alkyl", and "C 1-8 " is "C 1-8 Refers to "alkyl", and "C 0-8 " is "C 0-8 It refers to "alkyl," and the definitions for these are as previously stated.

[0145] "-C 0-8 Alkyl-S(O) r R8" is -S(O) r The sulfur atom in R8 is C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0146] "-C 0-8 In alkyl-O-R9", the oxygen atom in -O-R9 is C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0147] "-C 0-8 In alkyl-C(O)OR9", the carbonyl group in -C(O)OR9 is C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0148] "-C 0-8 Alkyl-C(O)R 10 "is -C(O)R 10 The carbonyl in it is C 0-8 It refers to being connected to an alkyl group, and C0-8 The definition of alkyl is as stated above.

[0149] "-C 0-8 Alkyl-OC(O)R 10 -OC(O)R 10 The oxygen atom in C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0150] "-C 0-8 Alkyl-NR 11 R 12 " is -NR 11 R 12 The nitrogen atom in C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0151] "-C 0-8 -C(=NR 11 )R 10 "is -C(=NR 11 )R 10 The carbon atom of C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0152] "-C 0-8 -N(R 11 )-C(=NR 12 )R 10 "is -N(R 11 )-C(=NR 12 )R 10 The nitrogen atom of C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0153] "-C 0-8 Alkyl-C(O)NR 11 R 12 "is -C(O)NR 11 R 12 The carbonyl of C 0-8 It refers to being connected to an alkyl group, and C 0-8The definition of alkyl is as stated above.

[0154] "-C 0-8 Alkyl-N(R 11 )-C(O)R 10 "is -N(R 11 )-C(O)R 10 The nitrogen atom in C 0-8 It refers to being connected to an alkyl group, and C 0-8 The definition of alkyl is as stated above.

[0155] Halogen substitution C 1-10 "Alkyl" refers to a 1 to 10-carbon alkyl group in which a hydrogen in the alkyl group is optionally substituted by 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.

[0156] Halogen substitution C 1-10 "Alkoxy" refers to a 1 to 10-carbon alkoxy group in which a hydrogen in the alkyl group is optionally substituted by a fluorine, chlorine, bromine, or iodine atom. It includes, but is not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.

[0157] Deuterium substitution C 1-10 "Alkyl" refers to a 1 to 10-carbon alkyl group in which a hydrogen in the alkyl group is optionally substituted by a deuterium atom. It includes, but is not limited to, monodeuteromethyl (-CH2D), diduteromethyl (-CHD2), trideuteromethyl (-CD3), etc.

[0158] Deuterium substitution C 1-10 "Alkoxy" refers to a 1 to 10-carbon alkyl group in which a hydrogen in the alkyl group is optionally substituted by a deuterium atom. It includes, but is not limited to, monodeuteromethoxy, diduteromethoxy, trideuteromethoxy, etc.

[0159] "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.

[0160] "Optional" or "optional" means that the event or situation described subsequently may occur but is not necessarily so, and includes cases where the event or situation occurs or does not occur, that is, two cases where it is substituted or is not substituted. For example, "optionally substituted heterocyclyl group" means that the alkyl may be present but is not necessarily so, and includes cases where the heterocyclyl group is substituted by an alkyl and cases where the heterocyclyl group is not substituted by an alkyl.

[0161] "Substituted" refers to a group of atoms in which one or more "hydrogen atoms" are independently substituted by a corresponding number of substituents. Needless to say, substituents exist only in possible chemical positions, and since this is consistent with the theory of chemical bonding, a person skilled in the art can identify possible or impossible substitutions (through experiment or theory) without excessive effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (e.g., an olefin).

[0162] "Stereo-isomers," whose English name is stereoisomer, refer to isomers formed depending on the arrangement of atoms within a molecule in space. These can be divided into two types: cis-trans isomers and enantiomers. They can also be broadly classified into two types: enantiomers and diastereomers. Stereoisomers resulting from the rotation of single bonds are called formational stereoisomers, and are sometimes referred to as rotamers. Stereoisomers resulting from causes such as bond length, bond angle, intramolecular double bonds, and rings are called configuration stereoisomers, and configuration stereoisomers are further divided into two types. Here, isomers formed due to the inability of a single bond of a carbon atom forming a double bond or ring to rotate freely are geometric isomers, also known as 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 if a compound of the present invention contains a double bond, it may be understood to contain the E and / or Z forms unless otherwise specified. Stereoisomers with different optical properties formed due to the lack of antiaxial symmetry within the molecule are called optical isomers and are divided into R and S configurations. Unless otherwise explained, the "stereoisomers" described in the present invention may be understood to include one or more of the enantiomers, configuration stereoisomers, and conformation stereoisomers.

[0163] In the present invention, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt or base addition salt comprising inorganic salts and organic salts, and such salts can be prepared by methods known in the art.

[0164] "Drug composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically usable salts or prodrugs and other chemical components, and other components, e.g., physiologically / pharmaceutically usable carriers and excipients. The purpose of the drug composition is to facilitate administration to a living organism, thereby aiding the absorption of the active ingredient and enabling it to exert biological activity.

[0165] The present invention will be described in more detail and completely below by combining examples, but this is not intended to limit the invention, and the invention is not limited to the contents of the examples.

[0166] 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) were expressed in parts per million (ppm). A Bruker AVANCE-400 / 500 nuclear magnetic resonance instrument was used for NMR analysis, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO- d 6 ), deuterium methanol (MeOH- d 4) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0167] Liquid chromatography mass spectrometry (LC-MS) measurements were performed using an Agilent 6120 mass spectrometer. HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid chromatography (Sunfire C18 150×4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150×4.6 mm chromatography column).

[0168] For thin-layer chromatography (TLC), Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates were used. The dimensions used for TLC were 0.15 mm to 0.20 mm, and the dimensions used for thin-layer chromatography for product separation and purification were 0.4 mm to 0.5 mm. For column chromatography, Yantai Yellow Sea silica gel with a mesh size of 200 to 300 was generally used as the carrier.

[0169] The starting materials used in the embodiments of the present invention may be known and commercially available, or may be synthesized by adopting or based on methods known in the art.

[0170] Unless otherwise noted, all reactions of the present invention are continuously stirred with a magnetic stirrer and carried out under a dry gaseous nitrogen or gaseous argon atmosphere, a dry solvent is used, and the unit of reaction temperature is degrees Celsius (°C).

[0171] 1. Preparation of intermediates

[0172] Intermediate 1: Preparation of 2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0173]

[0174] Step 1: Synthesis of 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0175]

[0176] 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 protection. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated saline solution, and dried with anhydrous sodium sulfate. After filtration and concentration, the solution was separated by column chromatography to obtain 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (2.15 g, yield: 95.2%). MS m / z (ESI): 349.2 [M+H] + .

[0177] Step 2: Synthesis of 2-Methoxy-5-Methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0178]

[0179] 1-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (1 g, 2.87 mmol) and Pd / C (50 mg, 10%) were added to 30 mL of methanol. After gas evacuation with hydrogen gas, the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere at atmospheric pressure. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and separated by column chromatography to obtain 2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (900 mg, yield: 98.5%). MS m / z (ESI): 319.2 [M+H] + .

[0180] Intermediate 2: Preparation of 2-Methoxy-5-Methyl-4-(4-Morpolinopiperidin-1-yl)aniline

[0181]

[0182] Step 1: Synthesis of 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)morpholine

[0183]

[0184] 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.73 g, 3.94 mmol) was added to DMSO (20 mL), and then K2CO3 (1.09 g, 7.89 mmol) and 4-(piperidin-4-yl)morpholine (0.81 g, 4.73 mmol) were added. The mixture was reacted overnight at 80°C, then the temperature was raised to 110°C and the mixture was reacted for 5 hours. After cooling to room temperature, the reaction mixture was extracted by adding dichloromethane and water. The organic phase was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography [developing solvent: CH2Cl2 / MeOH (+1% ammonia water) = 0–10%] to obtain 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)morpholine (1.23 g, yield: 80.9%). MS m / z (ESI): 336.0 [M+H] + .

[0185] Step 2: Synthesis of 2-Methoxy-5-Methyl-4-(4-Morpolinopiperidin-1-yl)aniline

[0186]

[0187] 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)morpholine (1.23 g, 3.18 mmol) was dissolved in methanol (10 mL), then Pd / C (0.10 g, 10%) was added, and after three hydrogen substitutions, the reaction was carried out overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through diatomite, and after concentrating the filtrate, the crude product was separated by column chromatography [developing solvent: CH2Cl2 / MeOH (+1% ammonia water) = 0–10%] to obtain 2-methoxy-5-methyl-4-(4-morpholinopiperidine-1-yl)aniline (0.81 g, yield: 80.2%). MS m / z (ESI): 306.2 [M+H] + .

[0188] Intermediate 3: Preparation of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0189]

[0190] Step 1: Synthesis of 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene

[0191]

[0192] 5-fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), then K2CO3 (969.16 mg, 7.01 mmol) and iodoethane (0.37 mL, 4.68 mmol) were added, and the mixture was stirred overnight. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline and dried with anhydrous sodium sulfate. By filtration and concentration, 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, yield: 90.2%) was obtained. MS m / z (ESI): 200 [M+H] + .

[0193] Step 2: Synthesis of 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0194]

[0195] 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene (420 mg, 2.11 mmol) was dissolved in DMSO (10 mL), then K2CO3 (582 mg, 4.22 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (580 mg, 3.16 mmol) were added, and the mixture was stirred overnight at 90 °C. After the reaction was complete, the reaction solution was diluted with water and extracted with dichloromethane; the organic phase was then washed with saturated saline and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (700 mg, yield: 91.6%). MS m / z (ESI): 363 [M+H] + .

[0196] Step 3: Synthesis of 2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0197]

[0198] 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (700 mg, 1.93 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1.03 g, 19.31 mmol) and Fe powder (1.08 g, 19.31 mmol) were added, and the mixture was stirred at 85 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (610 mg, yield: 95%). MS m / z (ESI): 333.2 [M+H] + .

[0199] Intermediate 4: Preparation of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0200]

[0201] Step 1: Synthesis of 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene

[0202]

[0203] 5-fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (10 mL), and Na2CO3 (743 mg, 7.01 mmol) was added. The reaction mixture was heated to 90°C, then ClCF2CO2Na (1247 mg, 8.18 mmol) was added, and the mixture was stirred for 3 hours while reacting at 90°C. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated saline solution and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, yield: 92.9%). MS m / z (ESI): 222.0 [M+H] + .

[0204] Step 2: Synthesis of 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0205]

[0206] 1-(difluoromethoxy)-5-fluoro-4-methyl-2-nitrobenzene (480 mg, 2.17 mmol) was dissolved in DMSO (10 mL), then K2CO3 (750 mg, 5.43 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (597 mg, 3.26 mmol) were added, and the mixture was stirred overnight at 90 °C. After the reaction was complete, the solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated saline and dried with anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to obtain 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (760 mg, yield: 91.1%). MS m / z (ESI): 385.0 [M+H] + .

[0207] Step 3: Synthesis of 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0208]

[0209] 1-(1-(5-(difluoromethoxy)-2-methyl-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (760 mg, 1.98 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1057 mg, 19.77 mmol) and Fe powder (1104 mg, 19.77 mmol) were added, and the mixture was stirred at 85 °C for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and separated by column chromatography to obtain 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (310 mg, yield: 44.2%). MS m / z (ESI): 355.0 [M+H] + .

[0210] Intermediate 5: Preparation of 5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)aniline

[0211]

[0212] Step 1: Synthesis of 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene

[0213]

[0214] 5-fluoro-4-methyl-2-nitrophenol (400 mg, 2.34 mmol) was dissolved in DMF (15 mL), and then K2CO3 (969 mg, 7.01 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.67 mL, 4.68 mmol) were added and stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline and dried with anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to obtain 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (560 mg, yield: 94.6%). MS m / z (ESI): 254.0 [M+H] + .

[0215] Step 2: Synthesis of 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidine-4-yl)piperazine

[0216]

[0217] 1-fluoro-2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)benzene (580 mg, 2.29 mmol) was dissolved in DMSO (15 mL), then 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 complete, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated saline solution and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)piperazine (900 mg, yield: 94.3%). MS m / z (ESI): 417.0 [M+H] + .

[0218] Step 3: Synthesis of 5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)aniline

[0219]

[0220] 1-methyl-4-(1-(2-methyl-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidine-4-yl)piperazine (900 mg, 2.16 mmol) was dissolved in methanol (20 mL) and water (5 mL), then NH4Cl (1156 mg, 21.61 mmol) and Fe powder (1207 mg, 21.61 mmol) were added, and the mixture was stirred at 85°C for 2 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated. The crude product was separated by column chromatography to obtain 5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (780 mg, yield: 93.4%). MS m / z (ESI): 387.0 [M+H] + .

[0221] Intermediate 6: Preparation of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0222]

[0223] Step 1: Synthesis of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0224]

[0225] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.40 g, 5.60 mmol) was dissolved in dimethylamine (10.0 mL), then K2CO3 (1.55 g, 11.20 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.54 g, 8.40 mmol) were added, and the mixture was heated to 100°C under nitrogen protection and stirred for 2 hours. After cooling to room temperature, the reaction mixture was extracted by adding dichloromethane and water, the organic phase was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was separated by column chromatography to obtain 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (2.20 g, yield: 92.9%). MS m / z (ESI): 413.0, 415.0 [M+H] + .

[0226] Step 2: Synthesis of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidine-4-yl)-4-methylpiperazine

[0227]

[0228] 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), then potassium vinyltrifluoroborate (259 mg, 1.94 mmol), Na2CO3 (308 mg, 2.90 mmol), and Pd(dppf)Cl2 (70.8 mg, 0.10 mmol) were added, and the mixture was stirred at 90°C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine (300 mg, yield: 86.0%). MS m / z (ESI): 361.0 [M+H] + .

[0229] Step 3: Synthesis of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0230]

[0231] 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidine-4-yl)-4-methylpiperazine (300 mg, 0.83 mmol) was dissolved in methanol (20 mL), then Pd / C (30 mg, 10%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere at atmospheric pressure. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (200 mg, yield: 72.3%). MS m / z (ESI): 333.2 [M+H] + .

[0232] Intermediate 7: Preparation of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0233]

[0234] Step 1: Synthesis of 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidine-4-yl)-4-methylpiperazine

[0235]

[0236] 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol) was dissolved in 1,4-dioxane (10 mL) and water (3 mL), then 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 stirred overnight at 90°C under nitrogen protection. The reaction mixture was cooled to room temperature, and extraction was performed by adding ethyl acetate and water. The organic phase was washed again with saturated saline and dried with sodium sulfate. After filtration and concentration, the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidine-4-yl)-4-methylpiperazine (0.26 g, yield: 61.0%). MS m / z (ESI): 375.2 [M+H] + .

[0237] Step 2: Synthesis of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0238]

[0239] 1-(1-(5-methoxy-4-nitro-2-(prop-1-en-2-yl)phenyl)piperidine-4-yl)-4-methylpiperazine (0.26 g, 0.57 mmol) was dissolved in methanol (10 mL), then Pd / C (0.05 g, 10%) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through diatomite, and the crude product obtained after concentrating the filtrate was separated by column chromatography [developing solvent: CH2Cl2 / MeOH (+1% ammonia water) = 0~10%) to obtain 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (0.14 g, yield: 67.7%). MS m / z (ESI): 347.2 [M+H] + .

[0240] Intermediate 8: Preparation of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0241]

[0242] Step 1: Synthesis of 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0243]

[0244] To a 10 mL toluene solution of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (0.40 g, 0.95 mmol), K3PO4 (0.60 g, 2.83 mmol), tricyclohexylphosphine (0.079 g, 0.28 mmol), Pd(OAc)2 (0.03 g, 0.14 mmol), and cyclopropyl boric acid (0.24 g, 2.83 mmol) were added, and the mixture was heated to 120 °C under nitrogen protection and reacted overnight. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added for extraction. The organic phase was washed again with saturated saline solution and dried with anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (0.28 g, yield: 68.5%). MS m / z (ESI): 375.2 [M+H] + .

[0245] Step 2: Synthesis of 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0246]

[0247] 1(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.28 g, 0.65 mmol) was dissolved in a mixed solution of methanol (8 mL) and water (2 mL), then Fe powder (0.18 g, 3.23 mmol) and NH4Cl (0.35 g, 6.47 mmol) were added, and the mixture was heated to 70°C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature and filtered through diatomite. The filtrate was concentrated, and the resulting crude product was separated by column chromatography to obtain 5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidin-1-yl)aniline (0.21 g, yield: 89.2%). MS m / z (ESI): 345.2 [M+H] + .

[0248] Intermediate 9: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-morpholinoaniline

[0249]

[0250] Step 1: Synthesis of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole

[0251]

[0252] 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (900 mg, 3.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.12 g, 5.4 mmol), K2CO3 (1.49 g, 10.8 mmol), and Pd(dppf)Cl2 (263 mg, 0.36 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL), heated to 100°C under nitrogen 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 again with saturated saline and dried with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to obtain 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (900 g, yield: 99.5%). MS m / z (ESI): 252.1 [M+H] + .

[0253] Step 2: Synthesis of 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)morpholine

[0254]

[0255] 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (150 mg, 0.60 mmol), K2CO3 (247.6 mg, 1.80 mmol), and morpholine (104 mg, 1.19 mmol) were added to DMSO (10 mL), heated to 100°C under nitrogen 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 again with saturated saline and dried with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to obtain 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)morpholine (160 mg, yield: 84.2%). MS m / z (ESI): 319.1 [M+H] + .

[0256] Step 3: Synthesis of 2-Methoxy-5-(1-Methyl-1H-Pyrazole-4-yl)-4-Morpolinoaniline

[0257]

[0258] 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)morpholine (160 mg, 0.52 mmol) was added to methanol (10 mL), followed by the addition of 10% Pd / C (20 mg), and the mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-morphollinoaniline (106 mg, yield: 68.3%). MS m / z (ESI): 289.1 [M+H] + .

[0259] Intermediate 10: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)aniline

[0260]

[0261] Step 1: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)-4-methylpiperazine

[0262]

[0263] 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (150 mg, 0.60 mmol), K2CO3 (248 mg, 1.80 mmol), and N-methylpiperazine (119 mg, 1.19 mmol) were added to DMSO (10 mL), heated to 100°C under nitrogen 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 again with saturated saline and dried with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to obtain 1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, yield: 75.8%). MS m / z (ESI): 332.1 [M+H] + .

[0264] Step 2: Synthesis of 2-Methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)aniline

[0265]

[0266] 1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)-4-methylpiperazine (150 mg, 0.45 mmol) was added to methanol (10 mL), followed by the addition of 10% Pd / C (20 mg), and the mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)aniline (68 mg, yield: 50.3%). MS m / z (ESI): 302.1 [M+H] + .

[0267] Intermediate 11: Preparation of 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0268]

[0269] Step 1: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0270]

[0271] 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.30 g, 1.19 mmol) was dissolved in dimethylamine (5 mL), then K2CO3 (0.50 g, 3.58 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (0.88 g, 4.78 mmol) were added, and the mixture was heated to 100°C under nitrogen protection and reacted 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 again with saturated saline solution and dried with anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (0.23 g, yield: 44.7%). MS m / z (ESI): 415.2 [M+H] + .

[0272] Step 2: Synthesis of 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0273]

[0274] 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine (0.23 g, 0.53 mmol) was added to methanol (10 mL), and 10% Pd / C (0.10 g) was added. The mixture was gas-exchanged with hydrogen and reacted overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through diatomite, and after concentrating the filtrate, the crude product was separated by column chromatography to obtain 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (0.16 g, yield: 72.7%). MS m / z (ESI): 385.2 [M+H] + .

[0275] Intermediate 12: Preparation of 5-fluoro-2-methoxy-4-[4-(4-methylpiperazine-1-yl)hexahydropyridine-1-yl]aniline

[0276]

[0277] Step 1: Synthesis of 1,2-Difluoro-4-Methoxy-5-Nitrobenzene

[0278]

[0279] Under ice bath cooling, 1,2-difluoro-4-methoxybenzene (1.626 mL, 13.88 mmol) was added to concentrated H2SO4 (6.81 g, 69.39 mmol) at 0°C, and then concentrated HNO3 (1.37 g, 15.27 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 3 hours. After the reaction was successfully completed, the reaction mixture was poured into ice water and extracted with EtOAc. The organic phase was then washed with a saturated aqueous solution of NaHCO3 and a saturated NaCl solution. The organic phase was combined, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was separated by silica gel column chromatography to obtain 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol, yield: 43.3%).

[0280] Step 2: Synthesis of 1-(1-(2-fluoro-5-methoxy-4-nitrophenyl)piperidine-4-yl)-4-methylpiperazine

[0281]

[0282] 1-methyl-4-(piperidin-4-yl)piperazine (1.10 g, 6.00 mmol) and DIPEA (1.94 g, 14.99 mmol) were added to a 1,4-dioxane (10 mL) solution of 4,5-difluoro-2-methoxy-1-nitrobenzene (1.14 g, 6.00 mmol), heated to 100°C under N2 protection, and stirred for 2 hours. After the reaction was successfully completed, it was cooled to room temperature. After concentrating the reaction mixture, the crude product 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridine-4-yl]-4-methylpiperazine was obtained and used in the next step of the reaction.

[0283] Step 3: Synthesis of 5-fluoro-2-methoxy-4-[4-(4-methylpiperazine-1-yl)hexahydropyridine-1-yl]aniline

[0284]

[0285] Methanol (8 mL) and water (2 mL) were added to the above 1-[1-(2-fluoro-5-methoxy-4-nitrophenyl)hexahydropyridine-4-yl]-4-methylpiperazine crude product (2.26 g, 5.99 mmol), followed by the addition of Fe powder (1.67 g, 29.95 mmol) and NH4Cl (3.20 g, 59.90 mmol). The mixture was heated to 75°C under N2 protection and stirred for 3 hours. After the reaction was fully completed, it was cooled to room temperature and filtered through diatomite. The filtrate was concentrated, water ammonia was added to the residue, extracted with dichloromethane, the organic phase was washed with saturated saline solution, and dried with anhydrous Na2SO4. The filtrate was filtered, concentrated, and separated by silica gel column chromatography to obtain 5-fluoro-2-methoxy-4-[4-methylpiperazine-1-yl)hexahydropyridine-1-yl]aniline (1.44 g, 4.42 mmol, yield: 73.9%). MS m / z (ESI): 323.2 [M+H] + .

[0286] Intermediate 13: Preparation of 5-chloro-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0287]

[0288] It was 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] + .

[0289] Intermediate 14: Preparation of 2,5-Dichloro-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0290]

[0291] It was prepared with 1,4-dichloro-2-fluorobenzene by referring to the preparation method of intermediate 12. MS m / z (ESI): 343.2 [M+H] + .

[0292] Intermediate 15: Preparation of 2-chloro-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline

[0293]

[0294] It was prepared with 1-chloro-5-fluoro-4-methyl-2-nitrobenzene by referring to the preparation method of intermediate 1. MS m / z (ESI): 323.2 [M+H] + .

[0295] Intermediate 16: Preparation of 4-(4-(4-ethylpiperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylaniline

[0296]

[0297] It was prepared by referring to the preparation method of Intermediate 1. MS m / z (ESI): 333.2 [M+H] + .

[0298] 2. Preparation of specific embodiments

[0299] Example 1: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0300]

[0301] Step 1: Synthesis of 2-(2-fluorophenyl)pyridine-4-amine

[0302]

[0303] 2-bromopyridine-4-amine (10 g, 57.80 mmol) and (2-fluorophenyl)boronic acid (9.70 g, 69.36 mmol) were dissolved in 1,4-dioxane (170 mL), and then an aqueous Na2CO3 solution (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 three times, then heated to 90°C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, saturated saline solution (600 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline solution and dried with anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was separated by column chromatography [eluent: EtOAc / PE=0–50%] to obtain 2-(2-fluorophenyl)pyridine-4-amine (10.0 g, yield: 92%). MS m / z (ESI): 189.0 [M+H] + .

[0304] Step 2: Synthesis of 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine

[0305]

[0306] 2-(2-fluorophenyl)pyridine-4-amine (5 g, 26.57 mmol) was added to DMF (50 mL), 60% NaH (1.59 g, 39.85 mmol) was added under cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. Then, 4,6-dichloropyrimidine (4.75 g, 31.88 mmol) was added under cooling in an ice bath, and the mixture was stirred overnight at room temperature. Ethanol was added to the reaction mixture, quenched, and concentrated. The crude product was separated by column chromatography to obtain 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (1 g, yield: 12.5%). MS m / z (ESI): 301.2 [M+H] + .

[0307] Step 3: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Synthesis of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0308]

[0309] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (50 mg, 0.17 mmol) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (63.5 mg, 0.2 mmol) were added to ethylene glycol monomethyl ether (3 mL), followed by the addition of a 4 M HCl / dioxane solution (0.17 mL, 0.67 mmol), and the mixture was stirred overnight at 120 °C. The reaction solution was neutralized with an NH3 / MeOH solution, concentrated, and separated by reverse-phase column chromatography to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine (21.5 mg, yield: 22.9%) was obtained. MS m / z (ESI): 583.2 [M+H]+ .

[0310] 1 1H NMR (400 MHz, MeOH- d 4) 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).

[0311] Example 2: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(2-methoxy-5-methyl-4-(4-morpholinopiperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0312]

[0313] 2-methoxy-5-methyl-4-(4-morpholinopiperidin-1-yl)aniline (0.24 g, 0.76 mmol) and 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (0.20 g, 0.64 mmol) were added to tert-butanol (10 mL), then p-toluenesulfonic acid monohydrate (0.60 g, 3.18 mmol) was added, and the mixture was heated to 100°C and reacted for 36 hours. The reaction solution was cooled to room temperature, neutralized and concentrated by adding water ammonia, and then the crude product was separated by column chromatography to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6-(2-methoxy-5-methyl-4-(4-morpholinopiperidine-1-yl)phenyl)pyrimidine-4,6-diamine (80 mg, yield: 41.1%) was obtained. MS m / z (ESI): 570.2 [M+H] + .

[0314] 1 HNMR (400 MHz, DMSO- d 6) 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).

[0315] Example 3: N 4 -(2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0316]

[0317] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (180 mg, 0.60 mmol) and 2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)aniline (219 mg, 0.66 mmol), NaO t Bu (115 mg, 1.20 mmol) and BrettPhos Pd-G3 (109 mg, 0.12 mmol) were added to toluene (10 mL), heated to 90°C under nitrogen protection, and stirred overnight. The reaction mixture was filtered, the filtrate was concentrated, and then separated by column chromatography to obtain the crude product. The crude product was further separated by passing it through a preparative column to obtain N 4 -(2-ethoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine (65 mg, yield: 18.0%) was obtained. MS m / z (ESI): 597.3 [M+H] + .

[0318] 1 ¹H NMR (400 MHz, DMSO- d 6 ) 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).

[0319] Example 4: N 4 -(2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0320]

[0321] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (200 mg, 0.67 mmol) and 2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-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 added to toluene (10 mL), heated to 90°C under nitrogen protection, and stirred overnight. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated and separated by column chromatography to obtain the crude product. It was then separated again using a preparative column to obtain N 4 -(2-(difluoromethoxy)-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine (25 mg, yield: 6.1%) was obtained. MS m / z (ESI): 619.3 [M+H] + .

[0322] 1 ¹H NMR (400 MHz, DMSO- d 6 ) 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).

[0323] Example 5: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrimidine-4,6-diamine

[0324]

[0325] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (53 mg, 0.18 mmol) and 5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (68 mg, 0.18 mmol), NaO t Bu (34 mg, 0.35 mmol) and BrettPhos Pd-G3 (16 mg, 0.02 mmol) were added to toluene (10 mL) and stirred overnight at 90°C under nitrogen protection. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated using a preparative column to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 -(5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-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] + .

[0326] 1 ¹H NMR (400 MHz, DMSO- d 6 ) 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).

[0327] Example 6: N 4 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0328]

[0329] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (100 mg, 0.33 mmol) and 5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-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 protection. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated and separated by column chromatography to obtain the crude product, and the crude product was further separated using a preparative column to obtain N4 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine (38 mg, yield: 19.2%) was obtained. MS m / z (ESI): 597.3 [M+H] + .

[0330] 1 ¹H NMR (400 MHz, DMSO- d 6 ) 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).

[0331] Example 7: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0332]

[0333] In a 10 mL toluene solution of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine 1-yl)piperidin-1-yl)aniline (0.14 g, 0.39 mmol), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine (0.12 g, 0.39 mmol), BrettPhos Pd-G3 (0.04 g, 0.04 mmol), and NaO t Bu (0.07 g, 0.77 mmol) was added, and the reaction was carried out overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography; the resulting crude product was then separated again using a preparative column to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 -(5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine (50.5 mg, yield: 21.3%) was obtained. MS m / z (ESI): 611.4 [M+H] + .

[0334] 1 HNMR (400 MHz, DMSO- d 6) 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).

[0335] Example 8: N 4 -(5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0336]

[0337] In a 10 mL toluene solution of 5-isopropyl-2-methoxy-4-(4-(4-methylpiperazine 1-yl)piperidin-1-yl)aniline (0.20 g, 0.55 mmol), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-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 reaction was carried out overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature, and the crude product obtained after concentration was separated by column chromatography. The obtained crude product was then separated again using a preparative column to N 4 -(5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine (96.8 mg, yield: 28.8%) was obtained. MS m / z (ESI): 609.4 [M+H] + .

[0338] 1 HNMR (400 MHz, DMSO- d 6) 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).

[0339] Example 9: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0340]

[0341] In a 10 mL toluene solution of 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidin-1-yl)aniline (0.16 g, 0.39 mmol), 6-chloro-N-(2-(2-fluorophenyl)pyridin-4-yl)pyrimidine-4-amine (0.12 g, 0.39 mmol), BrettPhos Pd-G3 (0.06 g, 0.07 mmol), and NaO t Bu (0.07 g, 0.78 mmol) was added, and the reaction was carried out overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography; the resulting crude product was then separated again using a preparative column to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 -(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine (65 mg, yield: 25.2%) was obtained. MS m / z (ESI): 649.4 [M+H] + .

[0342] 1 HNMR (400 MHz, DMSO-d 6) 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).

[0343] Example 10: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine

[0344]

[0345] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (100 mg, 0.33 mmol) and 2-methoxy-5-(1-methyl-1H-pyrazole-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), heated to 90°C under nitrogen protection, and stirred overnight. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated using a preparative column to obtain N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6-(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-morpholinophenyl)pyrimidine-4,6-diamine (40.5 mg, yield: 22.0%) was obtained. MS m / z (ESI): 553.2 [M+H] + .

[0346] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0347] Example 11: N 4 -(2-(2-fluorophenyl)pyridine-4-yl)-N 6 Preparation of -(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4,6-diamine

[0348]

[0349] 6-chloro-N-(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4-amine (62 mg, 0.21 mmol) and 2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-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 added to toluene (10 mL), heated to 90°C under nitrogen protection, and stirred overnight. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated and separated by column chromatography to obtain the crude product, which was then separated using a preparative column to obtain N 4-(2-(2-fluorophenyl)pyridine-4-yl)-N 6 -(2-methoxy-5-(1-methyl-1H-pyrazole-4-yl)-4-(4-methylpiperazine-1-yl)phenyl)pyrimidine-4,6-diamine (25.5 mg, yield: 21.9%) was obtained. MS m / z (ESI): 566.2 [M+H] + .

[0350] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.61 (s, 1H), 8.47-8.40 (m, 2H), 8.27 (s, 1H), 8.06 (s, 1H), 7.99 (t, J = 2.0 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).

[0351] Example 12: N 4 -(5-(2-fluorophenyl)pyridine-3-yl)-N 6 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0352]

[0353] Step 1: Synthesis of 5-(2-fluorophenyl)pyridine-3-amine

[0354]

[0355] Examples 1 It was manipulated by referring to Step 1 of.

[0356] Step 2: N 4 -(5-(2-fluorophenyl)pyridine-3-yl)-N 6 Synthesis of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine

[0357]

[0358] 4,6-dichloropyrimidine (60 mg, 0.40 mmol), 5-(2-fluorophenyl)pyridine-3-amine (76 mg, 0.40 mmol), and 2-methoxy-5-methyl-4-[4-(4-methylpiperazine-1-yl)piperidin-1-yl]aniline (130 mg, 0.40 mmol) were dissolved in anhydrous 1,4-dioxane (8 mL), and BrettPhos Pd-G3 (37 mg, 0.04 mmol) and NaO were added under nitrogen protection. t Bu (77 mg, 0.81 mmol) was added, and the mixture was heated to 85°C and reacted overnight. The reaction solution was cooled to room temperature, concentrated, and separated by column chromatography to obtain the crude product, which was then separated using a high-performance liquid-phase chromatography column to obtain N 4 -(5-(2-fluorophenyl)pyridine-3-yl)-N 6 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidine-4,6-diamine (14 mg, yield: 6.1%) was obtained. MS m / z (ESI): 583.2 [M+H] + .

[0359] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0360] Example 13: N 4 -(5-fluoro-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0361]

[0362] 6-chloro-N-[2-(2-fluorophenyl)pyridine-4-yl]pyrimidine-4-amine (101.6 mg, 0.338 mmol) and 5-fluoro-2-methoxy-4-[4-(4-methylpiperazine-1-yl)hexahydropyridine-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 reaction was carried out overnight at 130°C in a sealed tube under N2 protection. After cooling to room temperature, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography to N 4 -(5-fluoro-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 -(2-(2-fluorophenyl)pyridine-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] + .

[0363] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0364] Example 14: N 4 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0365]

[0366] Synthesized by referring to the preparation method of Example 13. MS m / z (ESI): 603.4 [M+H] + .

[0367] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.69 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.92 (td, J = 7.9, 1.7 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.46 (ddd, J = 7.6, 5.3, 1.9 Hz, 1H), 7.37 - 7.27 (m, 2H), 6.80 (s, 1H), 6.12 (s, 1H), 3.83 (s, 3H), 2.73 - 2.62 (m, 2H), 2.37 - 2.24 (m, 5H), 2.14 (s, 3H), 1.86 (d, J = 12.1 Hz, 2H), 1.65 - 1.51 (m, 2H).

[0368] Example 15: N 4 -(5-bromo-2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0369]

[0370] Synthesized by referring to the preparation method of Example 3. MS m / z (ESI): 647.4 [M+H] + .

[0371] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0372] Example 16: N 4 -(4-(4-(4-ethylpiperazine-1-yl)piperidine-1-yl)-2-methoxy-5-methylphenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0373]

[0374] Synthesized by referring to the preparation method of Example 3. MS m / z (ESI): 597.4 [M+H] + .

[0375] 1 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).

[0376] Example 17: N 4 -(2,5-dichloro-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0377]

[0378] Synthesized by referring to the preparation method of Example 13. MS m / z (ESI): 607.4 [M+H] + .

[0379] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0380] Example 18: N 4 -(2-chloro-5-methyl-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)-N 6 Preparation of -(2-(2-fluorophenyl)pyridine-4-yl)pyrimidine-4,6-diamine

[0381]

[0382] Synthesized by referring to the preparation method of Example 13. MS m / z (ESI): 587.4 [M+H] + .

[0383] 1 ¹H NMR (400 MHz, DMSO- d 6) 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).

[0384] Biological test evaluation

[0385] (Cell proliferation experiment)

[0386] (I) Reagents and Consumables

[0387] DMEM medium (Gibco, 11965118)

[0388] RPMI1640 medium (Gibco, 11875119)

[0389] Fetal bovine serum FBS (GBICO, Cat#10099-141)

[0390] CellTiter-Glo® Luminescence Cell Viability Analysis Kit (Promega, Cat#G7572)

[0391] Black transparent flat-bottom 96-well plate (Corning®, Cat# 3603)

[0392] (II) Device

[0393] SpectraMax Multi-Label Microplate Detector MD, 2104-0010A;

[0394] Carbon dioxide incubator, Thermo Scientific 3100 series;

[0395] Biosafety Cabinet, Thermo Scientific, 1300 Series Model A2;

[0396] Inverted microscope, Olympus, CKX41SF;

[0397] Siemens refrigerator, KK25E76TI.

[0398] (III) Cell System and Culture Conditions

[0399]

[0400] (IV) Experimental phase

[0401] 1. Cell Culture and Inoculation:

[0402] (1) Harvest cells during the logarithmic growth phase and count the cells using a platelet counter. Check cell viability by trypan blue exclusion to ensure that the cell viability is 90% or higher.

[0403] (2) Adjust the cell concentration to achieve the desired final density; add 90 μL of cell suspension to a 96-well plate.

[0404] (3) Incubate the cells overnight in a 96-well plate at 37°C, 5% CO2, and 95% humidity.

[0405] 2. T0 Reference Data:

[0406] (1) Add 10 μL of PBS to each well of the T0 plate containing the cells.

[0407] (2) Thaw the CTG reagent and equilibrate the cell plate at room temperature for 30 minutes.

[0408] (3) Add an equal volume of CTG solution to each well.

[0409] (4) Shake the cells in a rotary shaker for 5 minutes to divide them.

[0410] (5) To stabilize the fluorescence signal, leave the cell plate at room temperature for 20 minutes.

[0411] (6) Read the T0 fluorescence signal value.

[0412] 3. Dilution and Addition of Compounds

[0413] (1) According to the compound information table, a 10 mM stock solution is prepared by adding the corresponding volume of DMSO to the corresponding compound powder.

[0414] (2) Prepare compound solutions diluted 1000 times and 3.16 times.

[0415] (3) Prepare a 10x compound solution by diluting a 1000x diluted compound solution with PBS, with a maximum concentration of 10μM. Add 10μL of the drug to each well of a 96-well plate inoculated with 9 concentrations and 3.16x dilution, and inoculate cells. Set the concentration of each compound in duplicate in 3 wells, and the final concentration of DMSO is 0.1%.

[0416] (4) Cells are placed in a 96-well plate containing the drug at a temperature of 37°C, 5% CO2, and 95% humidity, and cultured for 72 hours, after which a CTG analysis is performed.

[0417] 4. Reading the fluorescence signal

[0418] (1) Thaw the CTG reagent and equilibrate the cell plate at room temperature for 30 minutes.

[0419] (2) Add an equal volume of CTG solution to each well.

[0420] (3) Break down the cells by shaking them in an orbital shaker for 5 minutes.

[0421] (4) To stabilize the fluorescence signal, leave the cell plate at room temperature for 20 minutes.

[0422] (5) Read the fluorescence signal value.

[0423] 5. Data Processing

[0424] Analyze the data using GraphPad Prism 7.0 software, obtain the capacity-effect curve by fitting the data using non-linear S-curve regression, and then accordingly IC 50 The value (unit: nM) is calculated, and the specific experimental results are as shown in Table 1.

[0425] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0426] Table 1: Biological test evaluation

[0427]

[0428] Based on the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have a potent inhibitory effect on EGFR Del19 mutations, EGFR L858R mutations, EGFR L858R / C797S double mutations, or EGFR Del19 / C797S double mutations at the cellular level, and have high selectivity for EGFR WT.

[0429] All literature mentioned in the present invention is cited as references in this application, just as each literature is cited alone as a reference. Furthermore, those skilled in the art should understand that various changes or modifications may be made to the present invention based on the above-mentioned content disclosed in the present invention, and that such equivalent forms are likewise included within the scope limited by the claims of this application.

Claims

Claim 1 Compounds of the following formula (III), stereoisomers thereof, or pharmaceutically acceptable salts thereof: ,where X1 and X2 are independently N or CH, respectively; Y is bonded, O, N(R 14 ) or C(R 15 R 16 ) and; R1 is selected from hydrogen, deuterium, halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, and isopropoxy, and said atomic group is independently optionally additionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, and bromine; R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azacyclobutyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and said atomic group is independently deuterium, methyl, ethyl, halogen substituted C 1-4 Alkyl, and deuterium-substituted C 1-4 Optionally further substituted by one or more substituents selected from alkyl; R 5a is selected from hydrogen, deuterium, fluorine, chlorine, and bromine;R 5e is selected from hydrogen, deuterium, fluorine, chlorine, and bromine;R 14 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, halogen-substituted C 1-4 Alkyl, and deuterium-substituted C 1-4 Selected from alkyl; R 15 and R 16 Each independently consists of hydrogen, deuterium, and C 3-6 Selected from cycloalkyl and 3-6-membered heterocyclyl, wherein the atomic group is deuterium, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, and deuterium-substituted C 1-4 A compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, optionally further substituted by one or more substituents selected from alkyl. Claim 2 A compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, azacyclobutyl, pyrazolyl, imidazolyl, oxazolyl, and triazolyl, and said atomic group is independently additionally substituted by one or more substituents selected from deuterium, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, and diduteriomethyl. Claim 3 In claim 1, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, hydroxyl, methoxyl, ethoxyl, and isopropoxy, and said atomic group is independently optionally additionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, and bromine; R 5a is hydrogen and;R 5e A compound of formula (III), stereoisomers thereof, or pharmaceutically acceptable salts thereof, characterized by being selected from hydrogen, deuterium, fluorine, chlorine, and bromine. Claim 4 In paragraph 1, R 14 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, and diduteriomethyl;R 15 and R 16 A compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that each is independently selected from hydrogen, deuterium, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, piperidinyl, morpholino, and piperazinyl, wherein the atomic group is optionally further substituted by one or more substituents selected from deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, and diduteriomethyl. Claim 5 In claim 1, the compound of formula (III), its stereoisomer, or its pharmaceutically acceptable salt, characterized by being selected from the following compounds: or . Claim 6 A method for preparing a compound of formula (III) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: Here, X is chlorine or bromine, and X1, X2, Y, R1, R2, R 5a and R 5e A method for preparing a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized as as defined in claim 1. Claim 7 A pharmaceutical composition for treating and / or preventing a tumor or metastatic disease at least partially associated with an EGFR Del19 mutation, an EGFR L858R mutation, an EGFR L858R / C797S double mutation, or an EGFR Del19 / C797S double mutation, comprising a compound of formula (III) according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically usable carrier. Claim 8 A pharmaceutical composition according to claim 7, wherein the tumor or metastatic disease is caused by a disorder inducing hyperproliferation and apoptosis. Claim 9 A pharmaceutical composition according to claim 7, wherein the tumor or metastatic disease is 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, urological tumor, skin tumor, sarcoma, nasal and sinus inverted papilloma or nasal and sinus inverted papilloma-associated nasal and sinus squamous cell carcinoma. Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete

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