EGFR mutation inhibitors and use thereof

Abstract

The present invention relates to EGFR mutation inhibitors and the use thereof. In particular, the present invention relates to EGFR mutation inhibitors having a structure of formula (I) and pharmaceutical compositions thereof, the use thereof as EGFR mutation inhibitors, and the use thereof in preparing drugs for treating carcinomas, tumors or metastatic diseases at least partially related to EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation, especially in preparing drugs for treating hyperproliferative diseases and cell death induction disorder diseases, the definition of each substituent in formula (I) being the same as the definition in the description.

Description

EGFR mutation inhibitor and its application Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to an EGFR mutation inhibitor and application thereof. Background Art

[0002] Lung cancer is the most lethal malignancy worldwide, posing a serious threat to human health. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Numerous molecular mechanisms, including gene mutations and dysregulation, have been implicated in the pathogenesis of NSCLC, with EGFR being a major driver gene. The global frequency of activating EGFR mutations in NSCLC patients is approximately 17%, with East Asian populations being more susceptible, with a mutation frequency of approximately 50%. Activating EGFR mutations primarily occur in exons 18-21, with deletion mutations in exon 19 (Del19) and the L858R point mutation in exon 21 being the most common subtypes, accounting for over 80% of all mutations. These mutations can lead to ligand-independent receptor activation and promote tumor cell survival and proliferation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) primarily target these two activating mutations. Compared with platinum-based chemotherapy, first- and second-generation EGFR TKIs can significantly prolong progression-free survival, but resistance often develops after 10-12 months of treatment. EGFR T790M mutation is the primary mechanism of resistance to first- and second-generation EGFR TKIs. Subsequently, the third-generation EGFR TKI osimertinib was developed to selectively inhibit EGFR T790M and common EGFR mutations. In the results of the Phase III FLAURA study, osimertinib demonstrated superior efficacy compared to first-generation EGFR TKIs, significantly improving progression-free survival (18.9 vs. 10.2 months) and overall survival (38.6 vs. 31.8 months), which directly propelled osimertinib into the first-line treatment cohort.

[0003] Despite the significant efficacy of osimertinib, drug resistance inevitably occurs and leads to disease progression. Currently, there are no approved targeted therapies for patients who develop resistance to osimertinib. Several EGFR-dependent and -independent resistance mechanisms have been reported in both preclinical and clinical studies. The C797X (most common is C797S) mutation on exon 20 has become the most common EGFR-dependent osimertinib resistance mechanism. The C797X mutation is located in the tyrosine kinase region of EGFR, preventing osimertinib from forming a covalent bond within the ATP-binding domain of EGFR, thereby producing drug resistance. In the Phase III AURA3 trial, the incidence of C797X mutations in patients receiving second-line osimertinib treatment was 15%, while in the Phase III FLAURA trial, the incidence of C797X mutations in patients receiving first-line osimertinib treatment was 7%. Therefore, developing a next-generation EGFR inhibitor with better activity and selectivity, targeting the double mutation consisting of EGFR activating mutation / C797S and the triple mutation consisting of EGFR activating mutation / T790M / C797S, is crucial for patients who have become resistant to first-line or second-line osimertinib.

[0004] Summary of the Invention

[0005] The present invention aims to provide an EGFR mutation inhibitor and its use. The series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation, and Del19 / T790M / C797S triple mutation. These compounds can be widely used to prepare drugs for treating cancers, tumors, or metastatic diseases at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation, and Del19 / T790M / C797S triple mutation, particularly drugs for treating hyperproliferative diseases and diseases that induce cell death, thereby potentially developing a new generation of EGFR mutation inhibitors.

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

[0007] Wherein, X is NR9 or O; L is a bond or -C≡C-;

[0008] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, amino, C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R15 substituted by a substituent;

[0009] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 AND-OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, hydroxyl, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl and -NR 16 R 17 substituted by a substituent;

[0010] R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 1-10 Alkylene, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent, provided that when R 3a and R 3b One of them is selected from C 1-10 When it is an alkylene group, the other is absent;

[0011] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0012] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0013] R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 ;

[0014] Each R7 and each R8 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 ;

[0015] R9 is selected from hydrogen, deuterium, cyano, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or R9 and R 3aand the directly connected part together form a 4-10 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl substituted C 1-10 Alkyl, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group substituted C 1-10 Alkyl, C 6-10 Aryl, C 6-10 Aryl-substituted C 1-10 Alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted C 1-10 Alkyl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0016] Each R 10 are each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)R 15 and -C 0-8 Alkyl-C(O)NR 16 R 17 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0017] Each R 11 and R 12 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or R 11 and R 12 Together with the sulfur atom directly connected thereto, a 3-10 membered heterocyclic group is formed, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R16 )-C(O)R 15 substituted by a substituent;

[0018] Each R 13 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0019] Each R 14 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0020] Each R 15 independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0021] Each R 16 and R 17 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, 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 heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0022] Or, R 16 and R 17 Together with the nitrogen atom directly connected thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, ═O, C 1-10 Alkyl, C 2-10Alkenyl, 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 heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0023] m and n are each independently 0, 1 or 2;

[0024] Each r is independently 0, 1 or 2.

[0025] As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0026] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxy;

[0027] R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent, provided that when R 3a and R 3b One of them is selected from C 1-4 When it is an alkylene group, the other is absent;

[0028] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0029] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0030] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 ;

[0031] Each R7 and each R8 are independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 ;

[0032] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl-substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 、-C 0-4 Alkyl-N=S(O)R 11 R 12 、-C 0-4 Alkyl-N=SR 11 R 12 、-C 0-4 Alkyl-OS(O)2R 13 、-C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)SR 14 、-C 0-4 Alkyl-SC(O)R 15 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-P(O)(R 15 )2. -C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0033] Among them, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0034] As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts, each R 10 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)R 15 and -C 0-4 Alkyl-C(O)NR 16 R 17 The above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0035] Each R 11 and R 12 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl or 5-8 membered heteroaryl, or R 11 and R 12 Together with the sulfur atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 、-C 0-4 Alkyl-OR 14 、-C 0-4 Alkyl-C(O)OR 14 、-C 0-4 Alkyl-C(O)R 15 、-C 0-4 Alkyl-OC(O)R 15 、-C 0-4 Alkyl-NR 16 R 17 、-C 0-4 Alkyl-C(=NR 16 )R 15 、-C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent;

[0036] Each R 13 independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0037] Each R 14 independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0038] Each R 15 independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent;

[0039] Each R 16 and R17 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, 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 substituted with an alkanoyl substituent;

[0040] Or, R 16 and R 17 Together with the nitrogen atom directly connected thereto, a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, 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 substituted with an alkanoyl substituent;

[0041] Each r is independently 0, 1 or 2.

[0042] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is a compound of formula (IIa):

[0043] Wherein, X is NR9 or O;

[0044] R1 is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0045] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxy;

[0046] R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent, provided that when R 3a and R 3b One of them is selected from C 1-4 When it is an alkylene group, the other is absent;

[0047] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0048] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0049] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl-substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、 -SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0050] Among them, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0051] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R1 is selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 aryl and substituted or unsubstituted 5-8 membered heteroaryl;

[0052] The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0053] The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of aryl and 5-8 membered heteroaryl are selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0054] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 substituted by a substituent;

[0055] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 ;

[0056] Among them, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0057] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IIIa):

[0058] Wherein, X is NR9 or O;

[0059] R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-10 Alkylene, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, halogen substituted C 1-10 Alkylene, deuterium substituted C 1-10 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0060] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-8 Aryl and 5-8 membered heteroaryl, or R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and the heteroaryl group are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl-substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16)-C(O)R 15 substituted by a substituent;

[0061] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 substituted by a substituent;

[0062] If the heterocyclic group or heteroaryl group in the above substituent definition does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur;

[0063] Among them, R1, R2, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0064] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IVa1):

[0065] Wherein, X is NR9 or O;

[0066] R 1a Selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 aryl and substituted or unsubstituted 5-8 membered heteroaryl;

[0067] The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0068] The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of aryl and 5-8 membered heteroaryl are selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0069] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl group;

[0070] R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkylene, deuterium substituted C 1-4 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0071] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, wherein the heteroatoms of the heterocyclic and heteroaryl groups are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl-substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0072] If the heterocyclic group or heteroaryl group in the above substituent definition does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur;

[0073] Among them, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17and r are as described for the compound of formula (I).

[0074] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1a Selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 aryl and substituted or unsubstituted 5-8 membered heteroaryl;

[0075] The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0076] The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of aryl and 5-8 membered heteroaryl are selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0077] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, wherein the heteroatoms of the heterocyclic and heteroaryl groups are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0078] If the heterocyclic group or heteroaryl group in the above substituent definition does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur;

[0079] Among them, R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0080] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, X is NR9; R9 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl and trideuteriomethyl.

[0081] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, X is O.

[0082] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R2 is methyl.

[0083] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 3a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethylene, difluoromethylene, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, oxolanyl, aziridine, azetidinyl and azetyl.

[0084] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1a Selected from the following groups:

[0085] 1) Substituted C 1-4 Alkyl, the C 1-4 The alkyl group is selected from methyl, ethyl, propyl and isopropyl, and the substituents of the methyl, ethyl, propyl and isopropyl groups are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0086] 2) Substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[3.4]octyl, Oxypropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, phenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyridinyl and pyrimidinyl, the above-mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[3.4]octyl, Oxypropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, The substituents of phenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyridinyl and pyrimidine are selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0087] Among them, R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0088] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1a Selected from the following groups:

[0089] 1) Substituted C 1-4 Alkyl, the C 1-4 The alkyl group is selected from methyl, ethyl, propyl and isopropyl, and the substituent of the methyl, ethyl, propyl or isopropyl group is selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0090] 2) Substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, The above cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, The substituent is selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0091] Among them, R 14 、R 15 、R 16 and R 17 As described for the compound of formula (I).

[0092] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1aSelect one or more R 18a substituted methyl, 1 or more R 18a Substituted ethyl, 1 or more R 18a Substituted propyl, 1 or more R 18a Substituted isopropyl,

[0093] Each R 18a are each independently selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0094] Each R 18b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0095] Each R 18c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0096] Each R 18d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0097] Each R 18e are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 ;

[0098] Each R 18f are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17;

[0099] Among them, R 14 、R 15 、R 16 and R 17 As described for the compound of formula (I).

[0100] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1a Select one or more R 18a Substituted methyl,

[0101] Each R 18a Each independently selected from fluoro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, piperazinyl, morpholinyl, 2-azaspiro [3.3] heptyl and hydroxy, the above groups are independently optionally further substituted by one or more selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, isopropyl substituted by a substituent selected from the group consisting of 2-azaspiro[3.3]heptanyl, ...

[0102] Each R 18b are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, cyano-substituted methyl, cyano-substituted ethyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, -OR 14a 、-OC(O)R 15a and -NR 16a R 17a ;

[0103] Each R 18cEach is independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuterioethyl, dideuterioethyl, trideuterioethyl, cyano-substituted methyl, cyano-substituted ethyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, azetyl, azetyl, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptanyl, methylsulfonyl, -OR 14a 、-C(O)OR 14a and -C(O)R 15a ;

[0104] Each R 18d are each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, methyl substituted with cyano, methyl substituted with hydroxy, -OR 14a 、-OC(O)R 15a and -NR 16a R 17a ;

[0105] Each R 18e each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, methyl substituted with cyano, and methyl substituted with hydroxy;

[0106] Each R 18f are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, cyano-substituted methyl, cyano-substituted ethyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, -OR 14a 、-OC(O)R 15a and -NR 16a R 17a ;

[0107] Each R 14a are each independently hydrogen, methyl, trifluoromethyl or trideuteriomethyl;

[0108] Each R 15a are each independently vinyl, methyl, ethyl, isopropyl or trifluoromethyl;

[0109] Each R 16a are each independently hydrogen or methyl;

[0110] Each R 17aare each independently hydrogen or methyl.

[0111] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IVa2):

[0112] Among them, R 1b Selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, wherein the heteroatoms of the heterocyclic and heteroaryl groups are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Substituted by cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, -SF5, hydroxyl, amino, methylamino, dimethylamino substituents;

[0113] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl group;

[0114] R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen, oxygen or sulfur, and the above C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 The group may be substituted by a cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclic oxy group, -SF5, a hydroxyl group, an amino group, a methylamino group, or a dimethylamino group.

[0115] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolanyl, oxacyclohexyl, azetyl and azacyclohexyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino;

[0116] R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl group, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino.

[0117] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R2 is methyl.

[0118] As a preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IIb):

[0119] Wherein, X is NR9 or O;

[0120] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0121] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxy;

[0122] R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、 -OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent, provided that when R 3a and R 3b One of them is selected from C 1-4 When it is an alkylene group, the other is absent;

[0123] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0124] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0125] R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ;

[0126] R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl-substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0127] Provided that, when R9 is selected from hydrogen or C 1-4 When alkyl, R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b At least one of them is selected from deuterium, fluorine substituted C 1-4 Alkyl or deuterium substituted C 1-4 Alkyl, or

[0128] R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2、-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent;

[0129] Among them, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and r are as described for the compound of formula (I).

[0130] As a preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0131] R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 ;

[0132] R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and -NR 16 R 17 ;

[0133] Among them, R 14 、R 15 、R 16 and R 17 As described for the compound of formula (I).

[0134] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IIIb1):

[0135] Among them, R 1cSelected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0136] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl group;

[0137] R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, fluorine-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkylene, deuterium substituted C 1-4 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0138] R9 is selected from deuterium, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-6 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and the heteroaryl group are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, =O, =S, -OR 14 、-C(O)OR 14 、-C(O)R 15、-OC(O)R 15 and -NR 16 R 17 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0139] If the heterocyclic group or heteroaryl group in the above substituent definition does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur;

[0140] Among them, R 14 、R 15 、R 16 and R 17 As described for the compound of formula (I).

[0141] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R9 is selected from deuterium, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, or R9 and R 3a and the directly connected part together form a 4-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen or oxygen, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, =O and -OR 14 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR14 、-C(O)R 15 、-OC(O)R 15 and -NR 16 R 17 substituted by a substituent;

[0142] Among them, R 14 、R 15 、R 16 and R 17 As described for the compound of formula (I).

[0143] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1c is selected from hydrogen, nitro, amino, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently optionally further substituted with one or more substituents selected from fluoro, chloro, cyano, methyl, ethyl, propyl and isopropyl;

[0144] R2 is a methyl group;

[0145] R 3a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethylene and difluoromethylene;

[0146] R9 is selected from cyano, cyclopropyl, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, or R9 and R 3a and the directly connected part together form a 6-membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen or oxygen, and the above groups are independently optionally further substituted by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and The above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl and acetyl.

[0147] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IIIb2):

[0148] Among them, R 1d phenyl or 5-6 membered heteroaryl, wherein the heteroatom of the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 substituted by alkoxy, amino, methylamino and dimethylamino substituents;

[0149] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl group;

[0150] R 3a is fluorine-substituted methyl or fluorine-substituted methylene;

[0151] R 5a and R 5b are each independently hydrogen or deuterium.

[0152] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1d phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 The alkyl group is substituted by a cycloalkyl group, a 3-6 membered heterocyclic group and an amino group.

[0153] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1d phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, and the above groups are independently optionally further substituted with one or more substituents selected from fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl and trideuteriomethyl;

[0154] R2 is a methyl group;

[0155] R 3a is monofluoromethyl, difluoromethyl, trifluoromethyl or monofluoromethylene;

[0156] R 5a and R 5b are each independently hydrogen or deuterium.

[0157] As a further preferred embodiment, among the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, the compound of formula (I) is the following compound of formula (IIIb3):

[0158] Among them, R 1e Selected from hydrogen, deuterium, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, wherein the heteroatoms of the heterocyclic and heteroaryl groups are selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 substituted by alkoxy, amino, methylamino and dimethylamino substituents;

[0159] R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl group;

[0160] R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 The alkylene group may be substituted by a cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclic oxy group, -SF5, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group.

[0161] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1e is selected from hydrogen, deuterium, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteriummethoxy, hydroxyl and amino;

[0162] R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl group, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino.

[0163] As a further preferred embodiment, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, R 1e is selected from hydrogen, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently optionally further substituted with one or more substituents selected from fluoro, chloro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteriomethoxy, hydroxyl and amino;

[0164] R2 is methyl; R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a cyclopropyl group, which is optionally further substituted by one or more fluorine groups.

[0165] As the most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:

[0166] The second aspect of the present invention provides a compound, its stereoisomers or pharmaceutically acceptable salts thereof including but not limited to the following compounds:

[0167] The third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0168] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating cancers, tumors or metastatic diseases that are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation.

[0169] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

[0170] 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 preparation of a medicament for treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinonasal inverted papilloma, or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma at least in part.

[0171] The present invention also relates to the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof for use as a medicament.

[0172] The present invention also relates to the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, for use in treating cancers, tumors or metastatic diseases that are at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation.

[0173] The present invention also relates to the use of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof for treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

[0174] The present invention also relates to the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, for use in treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation.

[0175] The present invention also relates to a method for treating cancer, tumor or metastatic disease at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation, which comprises administering a therapeutically effective amount of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof to a patient in need.

[0176] The present invention also relates to a method for treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders, which comprises administering a therapeutically effective amount of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof to a patient in need.

[0177] The present invention also relates to a method for treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinonasal inverted papilloma or sinonasal inverted papilloma-related squamous cell carcinoma of the nasal cavity and paranasal sinuses, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION

[0178] After extensive and in-depth research, the inventors of this application have developed, for the first time, an EGFR inhibitor having the structure of Formula (I) below. This series of compounds can be widely used to prepare medicaments for treating cancers, tumors, or metastatic diseases at least partially associated with the EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation, and Del19 / T790M / C797S triple mutation, and are expected to be developed into a new generation of EGFR mutation inhibitors. Based on this, the present invention was completed.

[0179] Detailed description

[0180] Unless stated to the contrary or specifically indicated otherwise, the following terms used in the specification and claims have the following meanings.

[0181] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or its various branched chain isomers, etc. “C 1-10 "Alkyl" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1-4 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups containing 1 to 4 carbon atoms, "C 0-8 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 0 to 8 carbon atoms, "C 0-4 The term "alkyl" refers to straight-chain and branched-chain alkyl groups having 0 to 4 carbon atoms.

[0182] Alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0183] "Alkylene" refers to a group of the formula "=R", wherein "R" is an "alkyl" group as defined above with two hydrogen atoms removed. Preferably, it includes straight-chain alkyl groups of 1 to 10, 1 to 6, or 1 to 4 carbon atoms and branched-chain alkyl groups with two hydrogen atoms removed, including but not limited to methylene (=CH2), ethylene (=CHCH3), hexylene (=CH(CH2)4CH3), and the like.

[0184] Alkylene may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0185] "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic aliphatic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Cycloalkyl is divided into monocyclic cycloalkyl and polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 to 6 carbon atoms. For example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 12 carbon atoms, "C 4-8 "Cycloalkyl" refers to a cycloalkyl group comprising 4 to 8 carbon atoms, "C 3-8 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 8 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0186] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0187] Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spiroalkyl" refers to a polycyclic group in which the rings share a carbon atom (called a spiro atom). These may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are classified as monospiroalkyl, bispiroalkyl, or polyspiroalkyl groups based on the number of spiro atoms shared between the rings. Spiroalkyl groups include, but are not limited to:

[0188] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with other rings 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 constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cycloalkyl groups include, but are not limited to:

[0189] "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These 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 constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0190] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0191] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0192] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic aliphatic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl are selected from N, O, N·O or S(O) r (wherein r is an integer of 0, 1, or 2), but excluding the ring portion of -OO-, -OS-, or -SS-, the remaining ring atoms are carbon. Preferably, the heterocyclyl group comprises 3 to 12, 3 to 8, or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl" refers to a heterocyclyl group comprising 3 to 6 ring atoms, "3-8 membered heterocyclyl" refers to a heterocyclyl group comprising 3 to 8 ring atoms, "4-8 membered heterocyclyl" refers to a heterocyclyl group comprising 4 to 8 ring atoms, "4-10 membered heterocyclyl" refers to a heterocyclyl group comprising 4 to 10 ring atoms, "5-8 membered heterocyclyl" refers to a heterocyclyl group comprising 5 to 8 ring atoms, and "3-12 membered heterocyclyl" refers to a heterocyclyl group comprising 3 to 12 ring atoms.

[0193] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0194] Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the single rings share an atom (called a spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O). r (where r is an integer 0, 1, or 2) with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are classified as monospiro heterocyclic groups, dispiro heterocyclic groups, or polyspiro heterocyclic groups based on the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0195] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O) r(where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, fused heterocyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused heterocyclic groups include, but are not limited to:

[0196] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N·O or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged heterocyclic groups include, but are not limited to:

[0197] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:

[0198] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0199] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 6-10 or 6-8 carbon atoms, for example, "C 6-10 "Aryl" refers to an all-carbon aromatic group containing 6-10 carbon atoms, including but not limited to phenyl and naphthyl. 6-8 "Aryl" refers to an all-carbon aromatic group containing 6-8 carbon atoms. The aromatic ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, including but not limited to:

[0200] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0201] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N·O and S(O)r (wherein r is an integer of 0, 1 or 2), preferably a heteroaromatic system containing 5-10, 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0202] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0203] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkenyl" refers to a straight or branched chain alkenyl containing 2 to 10 carbon atoms. 2-4 "Alkenyl" refers to a straight or branched chain alkenyl group containing 2 to 4 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0204] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0205] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, "C 2-10 "Alkynyl" refers to a straight or branched chain alkynyl containing 2 to 10 carbon atoms. 2-4 "Alkynyl" refers to a straight or branched chain alkynyl containing 2-4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.

[0206] "Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0207] "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms. 1-4"Alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms. 1-2 The term "alkoxy" refers to an alkyloxy group containing 1 to 2 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0208] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16)-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0209] "Cycloalkoxy" or "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkyloxy" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms. 3-6 The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 6 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0210] "Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8 Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0211] "Heterocyclyloxy" or "heterocyclyloxy" refers to an -O-heterocyclyl group wherein heterocyclyl is as defined above and includes, but is not limited to, azetidinyloxy, oxetanyloxy, azopentyloxy, nitrogen, oxhexyloxy, and the like.

[0212] "Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 、-C 0-8 Alkyl-N=S(O)R 11 R 12 、-C 0-8 Alkyl-N=SR 11 R 12 、-C 0-8 Alkyl-OS(O)2R 13 、-C 0-8Alkyl-S(O) r R 13 、-C 0-8 Alkyl-OR 14 、-C 0-8 Alkyl-C(O)OR 14 、-C 0-8 Alkyl-C(O)SR 14 、-C 0-8 Alkyl-SC(O)R 15 、-C 0-8 Alkyl-C(O)R 15 、-C 0-8 Alkyl-OC(O)R 15 、-C 0-8 Alkyl-P(O)(R 15 )2. -C 0-8 Alkyl-NR 16 R 17 、-C 0-8 Alkyl-C(=NR 16 )R 15 、-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 、-C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent.

[0213] “C 1-10 "Alkanoyl" refers to C 1-10 The monovalent atomic group remaining after removing the hydroxyl group from the alkyl acid is usually expressed as "C 0-9 "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionyl; "C3 alkyl-C(O)-" refers to butyryl or isobutyryl.

[0214] "-C 0-8 Alkyl-S(O)(=NR 10 )R 11 " refers to -S(O)(=NR 10 )R 11 The sulfur atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0215] "-C 0-8 Alkyl-N=S(O)R 11 R12 " refers to -N=S(O)R 11 R 12 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0216] "-C 0-8 Alkyl-N=SR 11 R 12 " refers to -N = SR 11 R 12 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0217] "-C 0-8 Alkyl-OS(O)2R 13 ” refers to -OS(O)2R 13 The oxygen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0218] "-C 0-8 Alkyl-S(O) r R 13 ” refers to -S(O) r R 13 The sulfur atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0219] "-C 0-8 Alkyl-P(O)(R 15 )2” refers to -P(O)(R 15 )2 in which the phosphorus atom is connected to the C 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0220] "-C 0-8 Alkyl-OR 14 " refers to -OR 14 The oxygen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0221] "-C 0-8 Alkyl-C(O)OR 14 " refers to -C(O)OR 14 The carbonyl group is connected to C 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0222] "-C 0-8 Alkyl-C(O)SR 14 ” refers to -C(O)SR 14 The carbonyl group is connected to C 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0223] "-C 0-8 Alkyl-SC(O)R 15 ” refers to -SC(O)R 15 The sulfur atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0224] "-C 0-8 Alkyl-C(O)R 15 ” refers to -C(O)R 15 The carbonyl group is connected to C 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0225] "-C 0-8 Alkyl-OC(O)R 15 ” refers to -OC(O)R 15 The oxygen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0226] "-C 0-8 Alkyl-NR 16 R 17 ”-NR 16 R 17 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0227] "-C 0-8 Alkyl-C(=NR 16 )R 15 " refers to -C(=NR 16 )R 15 The carbon atoms in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0228] "-C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 ” refers to -N(R 16 )-C(=NR 17 )R 15The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0229] "-C 0-8 Alkyl-C(O)NR 16 R 17 ” refers to -C(O)NR 16 R 17 The carbonyl group is connected to C 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0230] "-C 0-8 Alkyl-N(R 16 )-C(O)R 15 ” refers to -N(R 16 )-C(O)R 15 The nitrogen atom in the 0-8 On the alkyl group, where C 0-8 The alkyl group is as defined above.

[0231] "Halogen substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl and tribromomethyl.

[0232] "Halogen substituted C 1-10 "Alkoxy" refers to an alkoxy group of 1-10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms. It includes but is not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

[0233] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0234] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0235] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, i.e., includes both substituted and unsubstituted instances. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group.

[0236] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with chemical valence theory, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated bonds (such as olefins).

[0237] "Stereoisomers," whose English name is stereoisomer, refer to isomers resulting from the different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by rotation about single bonds are called conformational stereoisomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, the presence of double bonds or rings in the molecule are called configuration stereoisomers, which are further divided into two categories. Among them, isomers caused by the inability to rotate freely around double bonds or single bonds of ring carbon atoms are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotation properties due to the lack of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations. In this invention, "stereoisomers," unless otherwise specified, are understood to include one or more of the aforementioned enantiomers, configurational isomers, and conformational isomers.

[0238] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0239] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0240] The present invention will be further described in detail and completely below with reference to the embodiments, but the present invention is by no means limited thereto, and the present invention is not limited to the contents of the embodiments.

[0241] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0242] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0243] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0244] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0245] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures expressed in degrees Celsius (°C).

[0246] 1. Preparation of intermediates

[0247] Intermediate A1: Preparation of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0248] Step 1: Synthesis of tert-butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate

[0249] 2-Chloropyrimidin-4-amine (315 g, 2431.5 mmol) was dissolved in THF (3 L), and triethylamine (1183 mL, 85510.3 mmol), 4-dimethylaminopyridine (29.71 g, 243.2 mmol), and di-tert-butyl dicarbonate (1300 mL, 6078.7 mmol) were added. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was slurried with a mixed solvent of EA / PE (5%), filtered, and dried to yield tert-butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (667.2 g, yield: 75%). MS m / z (ESI): 330.4 [M+1] + .

[0250] Step 2: Synthesis of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0251] 1,2-Dihydro-3H-pyrazol-3-one (100 g, 1019 mmol) was dissolved in MeCN (1500 mL), and potassium carbonate (281.7 g, 2038.5 mmol) and 2-(trimethylsilyl)ethoxychloride (220.9 g, 1325 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was slurried with a mixture of ethyl acetate and petroleum ether (5%), filtered, and dried to yield 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (184.6 g, yield: 70%). MS m / z (ESI): 229.4 [M+1] + .

[0252] Step 3: Synthesis of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0253] 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (184.6 g, 0.806 mol) was dissolved in MeCN (1500 mL), and NBS (157.8 g, 0.89 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction as determined by LCMS, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was slurried with a mixture of EA / PE (5%), filtered, and dried to yield 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (153 g, yield: 61%). MS m / z (ESI): 337.4 [M+1] + .

[0254] Step 4: Synthesis of 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0255] 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one 10.0 g, 32.55 mmol) and tert-butyl (tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)carbamate (26.8 g, 81.36 mmol) were dissolved in acetonitrile / water (300 / 75 mL). Under a nitrogen atmosphere, sodium carbonate (10.35 g, 97.64 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (41.3 g, 162.73 mmol) and dichloro-di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (2.3 g, 3.26 mmol) were added. The reaction mixture was purged with nitrogen three times, and the reaction mixture was stirred at 100°C for four hours under a nitrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure to remove the solvent, and the residue was added to ethanol / water (200 / 200 mL). Potassium hydroxide (45.65 g, 813.65 mol) was added to the reaction mixture. The reaction mixture was stirred at 100°C overnight. The reaction mixture was concentrated to remove the organic solvent, diluted with water, and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was isolated by column chromatography (dichloromethane:methanol = 85%) to give 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (1.21 g, yield: 12%). MS m / z (ESI): 322.4 [M+1] + .

[0256] Intermediate A2: Preparation of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate

[0257] Step 1: Synthesis of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate

[0258] (Methoxymethyl)triphenylphosphonium chloride (90 g, 262.5 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium diisopropylamide (120 mL, 240.0 mmol) was added. The solution was reacted at 0°C for 2 hours, and then tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (25 g, 118.3 mmol) was added. The reaction solution was heated to 60°C and reacted for 10 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was separated using a flash silica gel column [0-6%: ethyl acetate: petroleum ether] to obtain tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (23 g, yield: 81.2%). MS m / z (ESI): 184.2 [M+1-56] + .

[0259] Step 2: Synthesis of tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate

[0260] Tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (23 g, 96.1 mmol) was dissolved in acetic acid (28 mL) and water (12 mL). The reaction mixture was heated to 20°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was separated using a flash silica gel column [0-10%: ethyl acetate: petroleum ether] to obtain tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (16 g, yield: 73.9%). MS m / z (ESI): 170.1 [M+1-56] + .

[0261] Step 3: Synthesis of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate

[0262] Dissolve tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (16 g, 71.0 mmol) in methanol (50 mL), then add potassium carbonate (20 g, 144.7 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (30.0 g, 156.2 mmol). Heat the reaction mixture to 20°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was separated using a flash silica gel column [0-10%: ethyl acetate: petroleum ether] to afford tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (13.0 g, yield: 82.8%). MS m / z (ESI): 166.1 [M+1-56] + .

[0263] Intermediate A3: Preparation of tert-butyl 4-ethynylpiperidine-1-carboxylate-4-d

[0264] Step 1: Synthesis of tert-butyl 4-(methoxymethylene)piperidine-1-carboxylate

[0265] (Methoxymethyl)triphenylphosphonium chloride (20.65 g, 60.23 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to 0°C. Under a nitrogen atmosphere, a solution of lithium diisopropylamide in tetrahydrofuran (31.619 mL, 63.237 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (6 g, 30.113 mmol) in tetrahydrofuran (100 mL) was then added. The reaction mixture was stirred at 60°C for 6 hours. Upon completion, the reaction mixture was concentrated to remove the solvent, diluted with water, and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography to provide tert-butyl 4-(methoxymethylene)piperidine-1-carboxylate (3.0 g, 13.2 mmol, yield: 43.9%). MS m / z(ESI):172.4[M-55] + .

[0266] Step 2: Synthesis of tert-butyl 4-formylpiperidine-1-carboxylate-4-d

[0267] Dissolve tert-butyl 4-(methoxymethylene)piperidine-1-carboxylate (0.5 g, 2.20 mmol) in deuterated water (0.6 mL) and acetic acid-d4 (1.4 mL). Stir the reaction mixture at 60°C for 72 hours. After the reaction is complete, remove the solvent, wash the residue with saturated sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to remove the solvent to obtain crude tert-butyl 4-formylpiperidine-1-carboxylate-4-d, which is used directly in the next reaction. MS m / z (ESI): 159.2 [M-55] + .

[0268] Step 3: Synthesis of tert-butyl 4-ethynylpiperidine-1-carboxylate-4-d

[0269] Dissolve tert-butyl 4-formylpiperidine-1-carboxylate-4-d (2.1 g, 9.80 mmol) in methanol (10 mL), cool to 0°C, and add dimethyl (1-diazo-2-oxopropyl)phosphonate (0.38 g, 2.0 mmol) and potassium carbonate (0.28 g, 2.0 mmol). Stir the reaction mixture at room temperature overnight. After completion of the reaction, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography to obtain tert-butyl 4-ethynylpiperidine-1-carboxylate-4-d (0.60 g, 2.15 mmol, yield: 21.9%). MS m / z (ESI): 155.2 [M-55] + .

[0270] 1 H NMR (400MHz, CDCl3) δ3.69 (ddd, J=13.3, 6.7, 3.6Hz, 2H), 3.19 (ddd, J=13.5, 8.4, 3.4Hz, 2H), 2.10 (s,1H),1.78(ddd,J=13.1,6.9,3.5Hz,2H),1.58(ddd,J=12.8,8.2,3.5Hz,2H),1.48-1.41(m,9H).

[0271] Intermediate A4: Preparation of tert-butyl 4-ethynyl-3-hydroxypiperidine-1-carboxylate

[0272] Step 1: Synthesis of tert-butyl 3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate

[0273] Dissolve trimethylsilylacetylene (12.86 mL, 90.34 mmol) in diethyl ether (450 mL) and cool to 0°C. Under a nitrogen atmosphere, slowly add n-butyllithium (36.14 mL, 90.34 mmol) and trimethylaluminum (41.41 mL, 82.81 mmol), and stir the mixture at room temperature for 15 minutes. Dissolve tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (15 g, 75.282 mmol) in diethyl ether (20 mL) and add the mixture. Cool the mixture to -78°C, slowly add boron trifluoride in diethyl ether (17 mL), and stir the reaction mixture at -78°C for 2 hours. Add methanol (45 mL), stir for 30 minutes, and then quench the reaction by adding saturated aqueous ammonium chloride (100 mL). Warm the mixture to room temperature and stir for 30 minutes. Add water (200 mL), and extract twice with diethyl ether (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a flash silica gel column [0-20%: ethyl acetate: petroleum ether] to afford tert-butyl 3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate (17.7 g, yield: 79.05%). MS m / z (ESI): 242.4 [M-55] + .

[0274] 1 H NMR (400MHz, CDCl3) δ3.99(dd,J=13.3,3.8Hz,1H),3.77(s,1H),3.59(s,1H),2.97(t,J=12.0Hz,2H),2.47(td,J=8.6,4.1Hz,1H),1.98-1.91(m,1H), 1.60-1.42(m,11H),0.30-0.09(m,9H).

[0275] Step 2: Synthesis of tert-butyl 4-ethynyl-3-hydroxypiperidine-1-carboxylate

[0276] Dissolve tert-butyl 3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate (17.7 g, 59.50 mmol) in methanol (100 mL), add potassium carbonate (8.22 g, 59.50 mmol), and stir the reaction mixture at room temperature for 3 hours. Filter, and evaporate the filtrate to remove the solvent under reduced pressure. The residue is washed with water and extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield tert-butyl 4-ethynyl-3-hydroxypiperidine-1-carboxylate (13.4 g, yield: 99.93%). MS m / z (ESI): 170.4 [M-55] + .

[0277] Intermediate A5: Preparation of tert-butyl 6-ethynyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

[0278] Under a nitrogen atmosphere, ethynylmagnesium bromide (79.52 mL, 39.76 mmol) was added to a round-bottom flask equipped with a stirrer and cooled to 0°C. Tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (7 g, 33.135 mmol) was dissolved in tetrahydrofuran (150 mL) and slowly added dropwise to the reaction flask. After the addition was complete, the reaction solution was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated using a flash silica gel column [0-25%:ethyl acetate:petroleum ether] to afford tert-butyl 6-ethynyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, yield: 45.79%). MS m / z (ESI): 96.4 [M-55]. + .

[0279] 1 H NMR (400MHz, CDCl3) δ4.01(s,2H),3.92(s,2H),2.72-2.61(m,2H),2.54(s,1H),2.49-2.36(m,2H),2.35-2.06(m,1H),1.43(s,9H).

[0280] Intermediate A6: Preparation of tert-butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0281] Dissolve tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 g, 47.34 mmol) in methanol (100 mL), then add potassium carbonate (13.08 g, 94.67 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (18.19 g, 94.67 mmol). The reaction mixture was heated to 20°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was separated using a flash silica gel column [0-25%: ethyl acetate: petroleum ether] to afford tert-butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (8.5 g, yield: 82.3%). MS m / z (ESI): 152.4 [M-55] + .

[0282] 1H NMR (400MHz, CDCl3) δ3.62 (d, J = 11.0 Hz, 2H), 3.35 (d, J = 11.1 Hz, 2H), 1.95-1.73 (m, 3H), 1.43 (d, J = 0.9 Hz, 9H).

[0283] Intermediate A7: Preparation of 4-ethynyl-1-methoxypiperidine

[0284] Step 1: Synthesis of dimethyl 3,3'-(methoxyazaalkanediyl)dipropionate

[0285] To a solution of sodium carbonate (6.98 g, 65.85 mmol) in anhydrous methanol (40 mL) was added methoxyamine hydrochloride (5 g, 59.87 mmol) and methyl acrylate (20.62 g, 239.46 mmol). The reaction mixture was stirred at 85°C overnight. The solvent was removed, and water and ethyl acetate were added. The organic layer was separated, further washed with saturated sodium chloride solution, and concentrated in vacuo. The residue was separated using a silica gel column [ethyl acetate:petroleum ether = 0-40%] to obtain dimethyl 3,3'-(methoxyazanediyl) dipropionate (8 g, yield: 60.95%).

[0286] Step 2: Synthesis of methyl 1-methoxy-4-oxopiperidine-3-carboxylate

[0287] To a solution of dimethyl 3,3'-(methoxyazanediyl)dipropionate (11 g, 50.17 mmol) in toluene (120 mL) was added sodium methoxide (5.69 g, 105.36 mmol). The reaction mixture was stirred at 130°C overnight. The reaction mixture was then cooled to 40°C, water (5 mL) was added, and stirred until completely dissolved. Concentrated hydrochloric acid (15 mL) was added and stirred for 10 minutes. The mixture was allowed to stand for separation, and the aqueous layer was used for the next reaction without purification.

[0288] Step 3: Synthesis of 1-methoxypiperidin-4-one

[0289] Concentrated hydrochloric acid (15 mL) was added to the aqueous solution from the previous step. The reaction mixture was stirred at 110°C overnight. The reaction mixture was then cooled to room temperature, the pH was adjusted to alkaline with sodium carbonate, and then a 4 mol / L aqueous sodium hydroxide solution (15 mL) was added. Finally, ethyl acetate was added for extraction to obtain an organic layer, which was further washed with a saturated sodium chloride solution and concentrated in vacuo. The residue was separated by silica gel column chromatography [ethyl acetate: petroleum ether = 0-40%] to obtain 1-methoxypiperidin-4-one (1.8 g, yield: 27.78%).

[0290] Step 4: Synthesis of 1-methoxy-4-(methoxymethylene)piperidine

[0291] To a solution of (methoxymethyl)triphenylphosphonium chloride (3.98 g, 11.61 mmol) in tetrahydrofuran (18 mL) was added a 2.5 M n-butyllithium solution (4.65 mL) with the temperature controlled at -60°C. After 20 minutes, 1-methoxypiperidin-4-one (1 g, 7.74 mmol) in tetrahydrofuran (9 mL) was added, and the reaction was stirred at 10°C for 2 hours. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The resulting organic layer was further washed with saturated sodium chloride solution and concentrated in vacuo. The residue was separated by silica gel column chromatography [ethyl acetate:petroleum ether = 0-20%] to afford 1-methoxy-4-(methoxymethylene)piperidine (473 mg, yield: 38.86%).

[0292] Step 5: Synthesis of 1-methoxypiperidine-4-carboxaldehyde

[0293] Concentrated hydrochloric acid (0.7 mL) was added to a solution of 1-methoxy-4-(methoxymethylene)piperidine (473 mg, 3.01 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated in vacuo and dried to give the crude product, which was carried out to the next step without purification.

[0294] Step 6: Synthesis of 4-ethynyl-1-methoxypiperidine

[0295] Potassium carbonate (3.34 g, 24.14 mmol) was added to a methanol solution (10 mL) of the crude product from the previous step, and the mixture was stirred at room temperature for 1 hour. Subsequently, dimethyl (1-diazo-2-oxopropyl)phosphonate (2.03 g, 10.56 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed, and the residue was separated by silica gel column chromatography [ethyl acetate:petroleum ether = 0-20%] to obtain 4-ethynyl-1-methoxypiperidine (150 mg, yield: 35.72%). MS m / z (ESI): 140.2 [M+1] + .

[0296] Intermediate A8: Preparation of tert-butyl 3-(1,1-difluoroprop-2-yn-1-yl)azetidine-1-carboxylate

[0297] Step 1: Synthesis of tert-butyl 3-(1-hydroxyprop-2-yn-1-yl)azetidine-1-carboxylate

[0298] At 0 ° C, under a nitrogen atmosphere, a solution of tert-butyl 3-formylazetidine-1-carboxylate (0.93 g, 5 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to ethynylmagnesium bromide (15 mL, 7.5 mmol), and the mixture was stirred at 0 ° C for 2 hours. The mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by a rapid silica gel column [eluent: ethyl acetate / petroleum ether: 0-15%] to give tert-butyl 3-(1-hydroxyprop-2-yn-1-yl)azetidine-1-carboxylate (0.9 g, yield: 85%). MS m / z (ESI): 156.2 [M-55] + .

[0299] Step 2: Synthesis of tert-butyl 3-propionylazetidine-1-carboxylate

[0300] To a solution of tert-butyl 3-(1-hydroxyprop-2-yn-1-yl)azetidine-1-carboxylate (4.5 g, 21.30 mmol) in ethyl acetate (50 mL) was added 2-iodoacylbenzoic acid (14.9 g, 53.25 mmol) at 0°C. The mixture was stirred at 80°C for 18 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-propionylazetidine-1-carboxylate (4.3 g, yield: 96%) as an oil, which was used directly in the next reaction.

[0301] 1 H NMR (400MHz, CDCl3) δ4.12-3.95 (m, 4H), 3.12 (ddd, J = 12.1, 6.0, 3.1Hz, 1H), 2.86 (t, J = 4.9Hz, 1H), 1.44 (s, 9H).

[0302] Step 3: Synthesis of tert-butyl 3-(1,1-difluoroprop-2-yn-1-yl)azetidine-1-carboxylate

[0303] To a solution of tert-butyl 3-propionylazetidine-1-carboxylate (2.0 g, 9.55 mmol) in dichloromethane (5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (8.8 mL, 47.79 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with dichloromethane and saturated sodium bicarbonate solution was added. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography [eluent: ethyl acetate / petroleum ether: 0-15%] to afford tert-butyl 3-(1,1-difluoroprop-2-yn-1-yl)azetidine-1-carboxylate (1.2 g, yield: 54%).

[0304] 1H NMR (400MHz, CDCl3) δ4.10-3.93 (m, 4H), 3.20-3.05 (m, 1H), 2.85 (t, J = 4.9Hz, 1H), 1.44 (s, 9H).

[0305] Intermediate B1: Preparation of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl 4-methylbenzenesulfonate

[0306] Step 1: Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

[0307] (R)-Butane-1,3-diol (10.0 g, 110.9 mmol) was dissolved in dichloromethane (150 mL), and imidazole (8.3 g, 122.1 mmol) was added. A solution of tert-butyldimethylsilyl chloride (16.7 g, 111.0 mmol) in dichloromethane (50 mL) was added dropwise at room temperature. The reaction mixture was allowed to react at room temperature for 18 hours. After completion, the reaction was diluted with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-12%:PE:EA] to obtain (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (18.2 g, yield: 80.2%).

[0308] 1 H NMR (400MHz, CDCl3) δ 3.99-3.90 (m, 1H), 3.87-3.70 (m, 2H), 3.16 (s, 1H), 1.65-1.51 (m, 2H), 1.11 (d, J = 6.3Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

[0309] Step 2: Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl 4-methylbenzenesulfonate

[0310] (R)-4-((tert-Butyldimethylsilyl)oxy)butan-2-ol (4.0 g, 26.2 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (2.38 g, 23.5 mmol) and 4-dimethylaminopyridine (0.48 g, 3.9 mmol) were added. A solution of 4-methylbenzenesulfonyl chloride (4.1 g, 31.5 mmol) in dichloromethane (10 mL) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-8%: petroleum ether: ethyl acetate] to afford (R)-4-((tert-Butyldimethylsilyl)oxy)butan-2-yl 4-methylbenzenesulfonate (4.0 g, yield: 57%). MS m / z (ESI): 359.3 [M+1] + .

[0311] Intermediate B2: Preparation of 3-((tert-butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate

[0312] 3-((tert-Butyldimethylsilyl)oxy)propan-1-ol (5.0 g, 26.2 mmol) was dissolved in THF (50 mL), and triethylamine (5.5 mL, 39.3 mmol) was added. A solution of 4-methylbenzenesulfonyl chloride (6.0 g, 31.5 mmol) in THF (20 mL) was added dropwise at room temperature. The reaction mixture was heated to 65°C for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-10%:PE:EA] to provide 3-((tert-Butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate (5.1 g, yield: 56.6%). MS m / z (ESI): 345.2 [M+1] + .

[0313] Intermediate B3: Preparation of (E)-4,4-difluorobut-2-enoic acid ethyl ester

[0314] Dissolve difluoroacetaldehyde hemiacetal (5.0 g, 39.65 mmol) in toluene (50 mL), then add ethoxycarbonylmethylenetriphenylphosphine (14.0 g, 40.2 mmol) and p-toluenesulfonic acid (689 mg, 4.0 mmol). Heat the reaction mixture to 120°C and react for 12 hours. After completion of the reaction, as determined by LCMS, dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (50 mL*3). The organic phase is washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. This affords crude (E)-4,4-difluorobut-2-enoic acid ethyl ester (4 g), which is used directly in the next reaction. MS m / z (ESI): 151.1 [M+1] + .

[0315] Intermediate B4: Preparation of ethyl (E)-4-fluorobut-2-enoate

[0316] Dissolve ethyl 2-fluoroacetate (11.56 mL, 118.76 mmol) in dichloromethane (150 mL), add diisobutylaluminum hydride (11.56 mL, 118.76 mmol) at -78 °C, and stir the reaction mixture for half an hour. Then add ethyl 2-(triphenyl-λ 5 The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. The resulting oil was slurried with petroleum ether, filtered, and the filtrate was concentrated to afford ethyl (E)-4-fluorobut-2-enoate (18.8 g), which was used directly in the next step.

[0317] Intermediate B5 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate B4:

[0318] Intermediate B6: Preparation of 2-(1-aminocyclopropyl)ethan-1-ol hydrochloride

[0319] Dissolve tert-butyl (1-(2-hydroxyethyl)cyclopropyl)carbamate (0.8 g, 3.98 mmol) in dichloromethane (10 mL). Add a solution of hydrochloric acid in 1,4-dioxane (6 mL, 24.0 mmol). Stir the mixture at room temperature overnight. The reaction mixture is concentrated under reduced pressure to remove the solvent, yielding 2-(1-aminocyclopropyl)ethan-1-ol hydrochloride (0.69 g, 99.87% yield).

[0320] Intermediate C1: Preparation of 2-chloro-N-cyclopropylpyridin-4-amine

[0321] 2-Chloro-4-fluoropyridine (1.7 g, 12.9 mmol) was dissolved in N-methylpyrrolidone (30 mL), followed by the addition of diisopropylethylamine (3.34 g, 25.85 mmol) and cyclopropylamine (0.96 g, 16.80 mmol). The reaction mixture was heated to 130°C for 2 hours. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-10%:ethyl acetate:petroleum ether] to afford 2-chloro-N-cyclopropylpyridin-4-amine (17.61 g, yield: 81.26%). MS m / z (ESI): 168.2 [M+1] + .

[0322] Intermediates C2 to C4 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate C1:

[0323] Intermediate C5: Preparation of tert-butyl 4-((4-((2-chloropyridin-4-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0324] Step 1: Synthesis of tert-butyl 4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0325] 4-Nitro-1H-pyrazole (4 g, 35.3 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydroxide (1.7 g, 42.4 mmol) was added at 0°C and stirred for 20 minutes. 4-(Bromomethyl)piperidine-1-carboxylic acid tert-butyl ester (9.8 g, 35.4 mmol) was added to the reaction mixture and heated to 80°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was slurried with a solvent (petroleum ether:ethyl acetate = 5:1, 60 mL) to isolate tert-butyl 4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (7.15 g, yield: 65.1%). MS m / z (ESI): 255.0 [M+1-56] + .

[0326] Step 2: Synthesis of tert-butyl 4-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0327] Dissolve tert-butyl 4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (7.15 g, 23.0 mmol) in methanol (150 mL) and tetrahydrofuran (60 mL), and add 10% Pd / C (0.5 g). The reaction mixture was allowed to react at room temperature under a H2 atmosphere for 18 hours. After completion of the reaction, as determined by LCMS, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent, yielding crude tert-butyl 4-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (7.01 g, yield: 100%). MS m / z (ESI): 281.2 [M+1] + .

[0328] Step 3: Synthesis of tert-butyl 4-((4-((2-chloropyridin-4-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0329] Tert-butyl 4-((4-amino-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (7.01 g, 25.0 mmol) was dissolved in N-methylpyrrolidone (75 mL), and N,N-diisopropylethylamine (9.69 g, 75.0 mmol) and 2-chloro-4-fluoropyridine (3.29 g, 25.0 mmol) were added. The reaction mixture was heated to 120°C for 24 hours. After completion of the reaction as determined by LCMS, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-50%: petroleum ether:ethyl acetate] to provide tert-butyl 4-((4-((2-chloropyridin-4-yl)amino)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (6.1 g, yield: 62.2%). MS m / z(ESI):392.2[M+1] + .

[0330] Intermediate C6: Preparation of 5-bromo-2-chloro-N-cyclopropylpyridin-4-amine

[0331] 5-Bromo-2,4-dichloropyridine (6 g, 26.446 mmol) was dissolved in N-methylpyrrolidone (50 mL), and N,N-diisopropylethylamine (10.25 g, 79.34 mmol) and cyclopropylamine (1.51 g, 26.45 mmol) were added. The reaction mixture was heated to 100°C overnight. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-13%:EA:PE] to obtain 5-bromo-2-chloro-N-cyclopropylpyridin-4-amine (9.5 g, yield: 71.6%). MS m / z (ESI): 246.1 [M+1]+ .

[0332] Intermediate D1: Preparation of (S)-N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-chloro-N-cyclopropylpyridin-4-amine

[0333] 2-Chloro-N-cyclopropylpyridin-4-amine (1.0 g, 5.93 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (0.71 g, 17.79 mmol) was added at 0°C. After stirring for 30 minutes, (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl 4-methylbenzenesulfonate (4.25 g, 11.861 mmol) was added. The reaction mixture was stirred at 0°C for 2.5 hours. After completion of the reaction, it was diluted with water (30 mL) and extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-10%: ethyl acetate: petroleum ether] to obtain (S)-N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-chloro-N-cyclopropylpyridin-4-amine (0.45 g, yield: 21.38%). MS m / z (ESI): 355.2 [M+1] + .

[0334] Intermediates D2 to D8 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate D1:

[0335] Intermediate E1: Preparation of ethyl 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutyrate

[0336] 5-Bromo-2-chloropyridin-4-amine (10.0 g, 48.20 mmol) was dissolved in N,N-dimethylformamide (50 mL), and (E)-4,4,4-trifluorobut-2-enoate (16.2 g, 96.36 mmol) was added. The reaction mixture was heated to 60°C for 1 hour. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-20%: ethyl acetate: petroleum ether] to obtain ethyl 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutanoate (8.7 g, yield: 48.06%). MS m / z (ESI): 375.1 [M+1]+.

[0337] Intermediates E2 to E5 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate E1.

[0338] Intermediate E6: Preparation of methyl (2-(4-(2-chloro-5-nitropyridin-4-yl)morpholin-3-yl)acetate

[0339] 2,4-Dichloro-5-nitropyridine (4.92 g, 25.50 mmol) was dissolved in tetrahydrofuran (50 mL), and methyl 2-(morpholin-3-yl) acetate hydrochloride (4.99 g, 25.50 mmol) and ethyldiisopropylamine (8.24 g, 63.74 mmol) were added. The reaction mixture was heated to 60°C overnight. After completion of the reaction, the solvent was removed from the reaction mixture, and the residue was separated using a preparative column chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to afford methyl (2-(4-(2-chloro-5-nitropyridin-4-yl)morpholin-3-yl) acetate (3.75 g, yield: 46.59%). MS m / z (ESI): 316.1 [M+1] + .

[0340] Intermediate F1: Preparation of 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutan-1-ol

[0341] Ethyl 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutanoate (8.7 g, 23.16 mmol) was dissolved in tetrahydrofuran (40 mL), and diisobutylaluminum hydride (47 mL, 47 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with a small amount of ethyl acetate. The solvent was then concentrated under reduced pressure to obtain 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutan-1-ol (10 g, crude product). MS m / z (ESI): 333.1 [M+1] + .

[0342] Intermediates F2 to F6 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate F1:

[0343] Intermediate F7: Preparation of 2-(1-((2-chloropyridin-4-yl)amino)cyclopropyl)ethan-1-ol

[0344] 2-(1-Aminocyclopropyl)-1-ethanol hydrochloride (0.69 g, 3.97 mmol) was dissolved in N-methylpyrrolidone (10 mL), followed by the addition of 2-chloro-4-fluoropyridine (1.04 g, 7.94 mmol) and potassium carbonate (2.74 g, 19.85 mmol). The mixture was heated to 120°C and allowed to react overnight. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-50%: ethyl acetate: petroleum ether] to afford 2-(1-((2-chloropyridin-4-yl)amino)cyclopropyl)ethan-1-ol (841 mg, yield: 99.60%). MS m / z (ESI): 213.2 [M+1] + .

[0345] Intermediate F8: Preparation of 2-(4-(5-bromo-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol

[0346] Step 1: Synthesis of 2-(4-(5-amino-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol

[0347] 2-(4-(2-chloro-5-nitropyridin-4-yl)morpholin-3-yl)ethan-1-ol (1 g, 1.55 mmol) was dissolved in ethanol (4 mL) and deionized water (1 mL). Iron powder (0.97 g, 17.38 mmol) and ammonium chloride (0.93 g, 17.38 mmol) were added. The reaction mixture was heated to 80°C for 3 hours. After completion of the reaction, the filtrate was filtered, diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-10% methanol:dichloromethane] to afford 2-(4-(5-amino-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol (0.73 g, yield: 81.49%). MS m / z(ESI):258.4[M+1] + .

[0348] Step 2: Synthesis of 2-(4-(5-bromo-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol

[0349] 2-(4-(5-amino-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol (400 mg, 1.55 mmol) was dissolved in acetonitrile (10 mL). tert-Butyl nitrite (320 mg, 3.10 mmol) was added at 0°C and stirred at room temperature for 1 hour. Cuprous bromide (143 mg, 3.104 mmol) was then added, and the reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the solvent was removed, and the residue was separated using a flash silica gel column [0-100%: ethyl acetate: petroleum ether] to afford 2-(4-(5-bromo-2-chloropyridin-4-yl)morpholin-3-yl)ethan-1-ol (274 mg, yield: 54.89%). MS m / z (ESI): 321.2 [M+1] + .

[0350] Intermediate F9: Preparation of (1-(((5-bromo-2-chloropyridin-4-yl)amino)methyl)cyclobutyl)methanol

[0351] 5-Bromo-2,4-dichloropyridine (31.51 g, 138.9 mmol) was dissolved in N-methylpyrrolidone (100 mL), followed by the addition of diisopropylethylamine (35.91 g, 277.80 mmol) and (1-(aminomethyl)cyclobutyl)methanol (16 g, 138.91 mmol). The reaction mixture was heated to 100°C for 18 hours. After completion of the reaction, the mixture was poured into water (150 mL). The precipitated solid was filtered, and the filter cake was washed with a small amount of acetonitrile and dried to afford (1-(((5-bromo-2-chloropyridin-4-yl)amino)methyl)cyclobutyl)methanol (33.6 g, yield: 79.16%). MS m / z (ESI): 305.0 / 307.0 [M+1] + .

[0352] Intermediate F10 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate F9:

[0353] Intermediate G1: Preparation of 5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloropyridin-4-amine

[0354] Dissolve 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutan-1-ol (10 g, 29.98 mmol) in dichloromethane (40 mL). Add imidazole (2.1 g, 30.85 mmol), 4-dimethylaminopyridine (378 mg, 3.09 mmol), and tert-butyldimethylsilyl chloride (4.7 g, 31.18 mmol). Stir the reaction mixture at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-20%: ethyl acetate: petroleum ether] to obtain 5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloropyridin-4-amine (10 g, yield: 74.48%). MS m / z (ESI): 447.2 [M+1] + .

[0355] Intermediates G2 to G9 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate G1:

[0356] Intermediate G10: Preparation of 5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloro-N-methylpyridin-4-amine

[0357] 5-Bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloropyridin-4-amine (50.0 g, 111.66 mmol) was dissolved in N-methylpyrrolidone (350 mL), and sodium tert-butoxide (21.46 g, 223.32 mmol) and iodomethane (17.4 mL, 279.14 mmol) were added. The reaction was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was separated using a flash silica gel column [0-7%:ethyl acetate:petroleum ether] to obtain 5-Bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloro-N-methylpyridin-4-amine (18.92 g, yield: 34.8%). MS m / z(ESI):461.4[M+1] + .

[0358] Intermediates G11 to G15 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate G10:

[0359] Intermediate H1: Preparation of ethyl 3-((6'-chloro-(2,3'-bipyridyl)-4'-yl)amino)-4,4,4-trifluorobutyrate

[0360] To a solution of ethyl 3-((5-bromo-2-chloropyridin-4-yl)amino)-4,4,4-trifluorobutyrate (3 g, 7.99 mmol) in toluene (50 mL) were added 2-(tributylstannyl)pyridine (3.23 g, 8.79 mmol) and tetrakis(triphenylphosphine)palladium (2.77 g, 2.40 mmol). Under a nitrogen atmosphere, the reaction mixture was heated to 110°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous potassium fluoride. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated using a silica gel column [0-30%:ethyl acetate:petroleum ether] to afford ethyl 3-((6'-chloro-(2,3'-bipyridinyl)-4'-yl)amino)-4,4,4-trifluorobutyrate (1.2 g, yield: 35.37%). MS m / z (ESI): 374.4 [M+1] + .

[0361] Intermediates H2 to H4 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate H1:

[0362] Intermediate I1: Preparation of 3-((6'-chloro-(2,3'-bipyridyl)-4'-yl)amino)-4,4,4-trifluorobutan-1-ol

[0363] To a solution of ethyl 3-((6'-chloro-(2,3'-bipyridyl)-4'-yl)amino)-4,4,4-trifluorobutanoate (800 mg, 2.140 mmol) in tetrahydrofuran (5 mL) was added diisobutylaluminum hydride (5.351 mL, 5.351 mmol, 1 M solution in n-hexane). The reaction mixture was allowed to react at room temperature for 1 hour. The reaction was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated using a silica gel column [0-50%: ethyl acetate: petroleum ether] to afford 3-((6'-chloro-(2,3'-bipyridyl)-4'-yl)amino)-4,4,4-trifluorobutan-1-ol (600 mg, yield: 81.12%). MS m / z (ESI): 332.4 [M+1] + .

[0364] Intermediates I2 to I5 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate I1:

[0365] Intermediate J1: Preparation of tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0366] Dissolve 5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-2-chloropyridin-4-amine (6.0 g, 13.4 mmol) in N,N-dimethylformamide (50 mL). Add tert-butyl 4-ethynylpiperidine-1-carboxylate (4.2 g, 20.1 mmol), bis(triphenylphosphine)palladium dichloride (1.88 g, 2.68 mmol), and triethylamine (18.62 mL). Heat the reaction mixture to 80°C for 18 hours. After the reaction was complete, the reaction solution was concentrated by LCMS, and the residue was separated using a flash silica gel column [0-30% ethyl acetate:petroleum ether] to obtain tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (6.0 g, yield: 73.83%). MS m / z (ESI): 576.6 [M+1] + .

[0367] Intermediate J2: Preparation of tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0368] (S)-5-Bromo-N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-chloropyridin-4-amine (1.0 g, 2.54 mmol) was dissolved in N,N-dimethylformamide (8 mL). Tert-butyl 4-ethynylpiperidine-1-carboxylate (0.96 g, 4.57 mmol), bis(triphenylphosphine)palladium dichloride (0.36 g, 0.51 mmol), and triethylamine (3.53 mL) were added. The reaction mixture was heated to 80°C for 18 hours. After the reaction was complete, the reaction solution was concentrated by LCMS, and the residue was separated using a flash silica gel column [0-30% ethyl acetate:petroleum ether] to obtain tert-butyl (S)-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (1.10 g, yield: 82.96%). MS m / z (ESI): 522.6 [M+1]. + .

[0369] Intermediates J3 to J6 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate J1 or J2:

[0370] Intermediate J7: Preparation of N-(4-((tert-butyldimethylsilyl)oxy)-1,1-difluorobutan-2-yl)-6'-chloro-(2,3'-bipyridyl)-4'-amine

[0371] 5-Bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1-difluorobutan-2-yl)-2-chloropyridin-4-amine (1.5 g, 3.490 mmol) was dissolved in 1,4-dioxane (15 mL), followed by the addition of 2-(tributylstannyl)pyridine (3.5 g, 9.507 mmol) and tetrakis(triphenylphosphine)palladium (520 mg, 0.450 mmol). The reaction mixture was heated to 110°C for 48 hours. After completion of the reaction, as determined by LCMS, the reaction mixture was concentrated, and the residue was separated using a flash silica gel column [0-70%:ethyl acetate:petroleum ether] to afford N-(4-((tert-butyldimethylsilyl)oxy)-1,1-difluorobutan-2-yl)-6'-chloro-(2,3'-bipyridyl)-4'-amine (350 mg, yield: 23.43%). MS m / z(ESI):428.1[M+1] + .

[0372] Intermediates J8-J9 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate J7:

[0373] Intermediate J10: Preparation of N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-6'-chloro-(2,3'-bipyridyl)-4'-amine

[0374] To a solution of 3-((6'-chloro-(2,3'-bipyridyl)-4'-yl)amino)-4,4,4-trifluorobutan-1-ol (600 mg, 1.81 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (246.28 mg, 3.62 mmol), tert-butyldimethylsilyl chloride (545.23 mg, 3.62 mmol), and 4-dimethylaminopyridine (132.59 mg, 1.085 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a silica gel column [0-20%: ethyl acetate: petroleum ether] to give N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)-6'-chloro-(2,3'-bipyridyl)-4'-amine (750 mg, yield: 87.39%). MS m / z (ESI): 446.5 [M+1] + .

[0375] Intermediates J11 to J14 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate J10:

[0376] Intermediate J15: Preparation of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-N-cyclopropyl-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-amine

[0377] Dissolve 5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-N-cyclopropylpyridin-4-amine (490 mg, 1.167 mmol) in dioxane and water (10 mL / 2.5 mL). Add 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194.3 mg, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (85 mg, 0.12 mmol), and potassium carbonate (484 mg, 3.5 mmol). Heat the reaction mixture to 100°C for 2 hours. After completion of the reaction, the product was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-40%: ethyl acetate: petroleum ether] to obtain N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-N-cyclopropyl-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-amine (89 mg, yield: 17.7%). MS m / z (ESI): 421.3 [M+1]. + .

[0378] Intermediate J16 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate J15:

[0379] Intermediate K1: Preparation of (S)-4-(4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)(cyclopropyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0380] (S)-N-(4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)-2-chloro-N-cyclopropylpyridin-4-amine (100 mg, 0.28 mmol) was dissolved in dioxane (10 mL), and then 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (99.61 mg, 0.55 mmol), sodium tert-butoxide (81.21 mg, 0.85 mmol), palladium acetate (12.65 mg, 0.06 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (70.16 mg, 0.11 mmol) were added. The reaction liquid was replaced with nitrogen three times and heated to 120°C for 2 hours. After the reaction was completed, the solvent was removed and the residue was separated using a flash silica gel column [0-20% methanol:dichloromethane] to give (S)-4-(4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)(cyclopropyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (40.21 mg, yield: 22.19%). MS m / z (ESI): 641.4 [M+1] + .

[0381] Intermediate K2 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate K1:

[0382] Intermediate K3: Preparation of tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0383] Tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (369.35 mg, 1.15 mmol) and 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (369.35 mg, 1.15 mmol) were added. A 9.35 mg, 1.15 mmol) suspension (9.35 mg, 1.15 mmol) was dissolved in dioxane (20 mL). Under a nitrogen atmosphere, sodium tert-butoxide (369.35 mg, 1.149 mmol) and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (208.31 mg, 0.23 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 120°C under a nitrogen atmosphere for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by flash silica gel column chromatography [0-10%: dichloromethane: methanol] to give tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (420 mg, yield: 40.7%). MS m / z (ESI): 808.2 [M+1] + .

[0384] Intermediates K4 to K22 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate K3:

[0385] Intermediate K23: Preparation of tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0386] Tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (750 mg, 1.30 mmol) was dissolved in dioxane (10 mL), and 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 , 2-dihydro-3H-pyrazol-3-one (418.44 mg, 1.30 mmol), cesium carbonate (1272.36 mg, 3.91 mmol), tris(dibenzylideneacetone)dipalladium (237.9 mg, 0.26 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (300.6 mg, 0.52 mmol), the reaction liquid was replaced with nitrogen three times, and heated to 115°C for 1 hour. After the reaction was completed, the solvent was removed and the residue was separated using a flash silica gel column [0-10% methanol:dichloromethane] to give tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (401 mg, yield: 17.879%). MS m / z (ESI): 861.4 [M+1] + .

[0387] Intermediates K24 to K25 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate K23:

[0388] Intermediate K26: Preparation of 4-(4-((5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)(methyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0389] 5-Bromo-N-(4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)2-chloro-N-methylpyridin-4-amine (5 g, 10.83 mmol) was dissolved in dioxane (150 mL), and then 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (3.87 g, 10.82 mmol), sodium tert-butoxide (2.08 g, 21.65 mmol), tris(dibenzylideneacetone)dipalladium (1.98 g, 2.16 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene (2.05 g, 4.33 mmol) were added. The reaction liquid was replaced with nitrogen three times and heated to 80°C for 18 hours. After the reaction was completed, the solvent was removed and the residue was separated using a flash silica gel column [0-90%: ethyl acetate: petroleum ether] to give 4-(4-((5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)(methyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (6.2 g, yield: 69.1%). MS m / z (ESI): 746.8, 747.8 [M+1]. + .

[0390] Intermediates K27 to K33 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate K26.

[0391] Intermediate L1: Preparation of tert-butyl 4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0392] Tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (200.5 mg, 0.23 mmol) was dissolved in THF (5 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 mL, 1.00 mmol) was added, and the mixture was heated to 60° C. and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated using a flash silica gel column [0-15%: dichloromethane: methanol] to obtain tert-butyl 4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (70 mg, yield: 48.76%). MS m / z (ESI): 617.8 [M+1] + .

[0393] Intermediate L2: Preparation of tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0394] Tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (404 mg, 0.50 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 mL, 1.00 mmol) was added, and the mixture was heated to 60° C. and stirred for 18 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated using a flash silica gel column [0-15%: dichloromethane: methanol] to obtain tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (93 mg, yield: 29.72%). MS m / z (ESI): 563.8 [M+1] + .

[0395] Intermediates L3 to L26 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediates L1 or L2.

[0396] Intermediate L27: Preparation of 4-(4-((5-bromo-4-(methyl(1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol

[0397] Dissolve 4-(4-((5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluorobutan-2-yl)(methyl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (5 g, 5.46 mmol) in dichloromethane (35 mL) and add trifluoroacetic acid (15 mL). Heat to 50°C and react for 2 hours. After completion of the reaction, remove the solvent. The residue was separated by preparative column chromatography [0-15%: dichloromethane:methanol] to give 4-(4-((5-bromo-4-(methyl(1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (1.86 g, yield: 69.79%). MS m / z (ESI): 504.4, 502.4 [M+1] + .

[0398] Intermediates L28 to L33 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate L27:

[0399] Intermediate M1: tert-butyl 4-((1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 Preparation of 1-methyl)ethynyl)piperidine-1-carboxylate

[0400] Tert-butyl 4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (68 mg, 0.11 mmol) was dissolved in toluene (5 mL) and cyanomethylenetri-n-butylphosphine (159.69 mg, 0.66 mmol) was added. The reaction solution was replaced with nitrogen three times and heated to 135°C for 18 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [0-10%: dichloromethane: methanol] to give tert-butyl 4-((1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidine-1-carboxylate (65.0 mg, yield: 98.4%). MS m / z (ESI): 599.8 [M+1] + .

[0401] Intermediate M2: tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 Preparation of 1-methyl)ethynyl)piperidine-1-carboxylate

[0402] Tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (90 mg, 0.16 mmol) was dissolved in toluene (5 mL) and cyanomethylenetri-n-butylphosphine (231.64 mg, 0.96 mmol) was added. The reaction solution was replaced with nitrogen three times and heated to 135°C for 18 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [0-10%: dichloromethane: methanol] to give tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidine-1-carboxylate (85.0 mg, yield: 97.57%). MS m / z (ESI): 545.7 [M+1] + .

[0403] Intermediates M3 to M5 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediates M1 or M2:

[0404] Intermediate M6:4 5 -Br-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0405] 4-(4-((5-bromo-4-(methyl(1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (900 mg, 1.84 mmol) was dissolved in toluene (6 mL) and cyanomethylenetri-n-butylphosphine (2.67 g, 11.06 mmol) was added. The reaction solution was replaced with nitrogen three times and heated to 135°C for 18 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [0-10%: dichloromethane: methanol] to obtain 4 5 -Br-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (410 mg, yield: 47.30%). MS m / z (ESI): 484.4, 486.4 [M+1] + .

[0406] Intermediates M7 to M13 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate M6:

[0407] Intermediate N1: tert-butyl 4-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 Preparation of 1-methyl)ethynyl)piperidine-1-carboxylate

[0408] 4 5 -Br-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (130 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (4 mL), and tert-butyl 4-ethynylpiperidine-1-carboxylate (260 mg, 1.24 mmol), cuprous iodide (106 mg, 0.56 mmol), cesium carbonate (400 mg, 1.23 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (202 mg, 0.22 mmol) and triethylamine (1 mL) were added. The reaction liquid was replaced with nitrogen three times and heated to 105°C for 6 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [0-10%: dichloromethane: methanol] to obtain tert-butyl 4-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidine-1-carboxylate (165 mg, yield: 99.52%). MS m / z (ESI): 613.6 [M+1] + .

[0409] Intermediates N2 to N28 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate N1:

[0410] Intermediate N29: tert-butyl 6-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 Preparation of 6-fluoro-2-azaspiro[3.3]heptane-2-carboxylate

[0411] At 0 ° C, tert-butyl 6-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5To a solution of dichloromethane (5 mL) of bis(2-methoxyethyl)aminosulfur trifluoride (0.47 mL, 2.55 mmol) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.47 mL, 2.55 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with dichloromethane and a saturated sodium bicarbonate solution was added. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by a rapid silica gel column [eluent: ethyl acetate / petroleum ether: 0-15%] to obtain tert-butyl 6-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)-6-fluoro-2-azaspiro[3.3]heptane-2-carboxylate (102 mg, yield: 63.55%). MS m / z (ESI): 643.8 [M+1] + .

[0412] Intermediates N30 to N33 can be prepared by selecting corresponding raw materials according to the synthesis method of intermediate N29:

[0413] Intermediate P1:1 1 -methyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0414] Tert-butyl 4-((1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidine-1-carboxylate (110.0 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), and a dioxane solution of hydrochloric acid (1 mL, 4.0 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain 1 1 -methyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (91.6 mg, yield: 100%). MS m / z (ESI): 499.6 [M+1] + .

[0415] Intermediate P2: (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ylethynyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0416] Tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidine-1-carboxylate (85 mg, 0.156 mmol) was dissolved in dichloromethane (3 mL), and a dioxane solution of hydrochloric acid (1 mL, 4 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ylethynyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (69.0 mg, yield: 99.4%). MS m / z (ESI): 445.6 [M+1] + .

[0417] Intermediates P3 to P12 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediates P1 or P2:

[0418] Intermediate P13: 6-(difluoromethyl)-1 1 ,5-dimethyl-4 5 -(piperidin-4-ethynyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane trifluoroacetate

[0419] tert-butyl 4-((6-(difluoromethyl)-1 1 -methyl-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 6-(difluoromethyl)-1-piperidin-1-yl)ethynyl)piperidin-1-carboxylate (165 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. Stir at room temperature for 1 hour. After the reaction was complete, the solvent was removed. The residue was slurried with ethyl acetate and petroleum ether to obtain 6-(difluoromethyl)-1-piperidin-1-yl)ethynyl)piperidin-1-carboxylate (165 mg, 0.28 mmol) 1 ,5-dimethyl-4 5 -(piperidin-4-ethynyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane trifluoroacetate (60 mg, yield: 35.59%). MS m / z (ESI): 495.6 [M+1] + .

[0420] Intermediates P14 to P28 can be prepared by selecting the corresponding raw materials according to the synthesis method of intermediate P13.

[0421] 2. Preparation of Specific Examples

[0422] Example 1: (S)-5-cyclopropyl-1 1 ,6-dimethyl-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0423] ((S)-4-(4-((4-(cyclopropyl(4-hydroxybutan-2-yl)amino)pyridin-2-yl)amino)pyrimidin-2-yl)-1-methyl-1H-pyrazol-5-ol (25.0 mg) was dissolved in toluene (5 mL), and cyanomethylenetri-n-butylphosphine (61.03 mg, 0.25 mmol) was added. The reaction solution was nitrogen-purged three times and heated to 135° C. for 18 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to give ((S)-5-cyclopropyl-1 1 ,6-dimethyl-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (2.0 mg, yield: 10.3%). MS m / z (ESI): 378.2 [M+1] + .

[0424] 1 H NMR (400MHz, DMSO-d6) δ9.78(S,1H),8.52(d,J=2.3Hz,1H),8.23(d,J=5.8Hz,1H),7.92(d,J=5.0Hz,2H),6.75(d,J=6.75Hz,,1H),6.69(d,J=6.7Hz ,1H),4.39(td,J=9.6,2.4Hz,1H),4.29-4.17(m,,2H),3.76(s,3H),2.17- 1.96(m,3H),1.49(d,J=6.9Hz,3H),0.95-0.83(m,4H),0.25-0.15(m,1H).

[0425] Examples 2 to 22, comparative compound 1 and comparative compound 3 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 1:

[0426] The NMR data of the compound prepared in the above example are as follows:

[0427] Example 24: (S)-1 1 ,6-dimethyl-5-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0428] (S)-4-((4-(1 1 ,6-dimethyl-1 1 Tert-butyl (H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-5-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (155 mg, 0.26 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and hydrochloric acid / dioxane (2.5 mL, 4 mol / L) was added. The reaction solution was reacted at room temperature for 2 hours. After LCMS detection, the reaction was concentrated under reduced pressure to remove the solvent to obtain (S)-1 1 ,6-dimethyl-5-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-11 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (145 mg, yield: 104%). MS m / z (ESI): 501.6 [M+1] + .

[0429] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.47(d,J=2.4Hz,1H),8.25(d,J=5.8Hz,1H),7.92(s,1H),7.82( s,1H),7.72(d,J=5.9Hz,1H),7.40(s,1H),6.75(d,J=5.8Hz,1H),5.82(dd,J=6.0,2.3Hz,1H),4.58(d ,J=9.6Hz,2H),4.32-4.25(m,1H),3.98(d,J=7.2Hz,2H),3.77(s,3H),2.91(d,J=12.0Hz,2H),2.39(d ,J=11.7Hz,2H),2.24-2.12(m,1H),1.85(d,J=24.5Hz,2H),1.39(d,J=12.6Hz,2H),1.12-1.05(m,5H).

[0430] Examples 25 to 26 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 24:

[0431] The NMR data of the compound prepared in the above example are as follows:

[0432] Example 27:1 1 ,5-dimethyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyridin-4(2,4)-pyrimidin-1(4,5)-pyrazoloheterocyclononane

[0433] Tert-butyl 4-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5-yl)ethynyl)piperidine-1-carboxylate (165 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. Stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed. The residue was slurried with ethyl acetate and petroleum ether to obtain 1 1 ,5-dimethyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyridin-4(2,4)-pyrimidin-1(4,5)-pyrazoloheterocyclononane (60 mg, yield: 35.59%). MS m / z (ESI): 513.6 [M+1] + .

[0434] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8.10(s,1 H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.69(t,J=9.2Hz,1H),4.44(t,J=10.9Hz,1H ),4.29(d,J=9.9Hz,1H),3.77(s,3H),3.13(s,3H),2.92(d,J=12.7Hz,2H),2.75(s, 1H), 2.57 (t, J = 11.1Hz, 2H), 2.39 (d, J = 13.2Hz, 2H), 1.79 (s, 2H), 1.55-1.45 (m, 2H).

[0435] Examples 28 to 30 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 27:

[0436] The NMR data of the compound prepared in the above example are as follows:

[0437] Example 31:1 1 -methyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0438] 1 1 -methyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (15 mg, 0.03 mmol) was dissolved in methanol (3 mL), and aqueous formaldehyde solution (0.5 mL, 37% mass fraction) was added. The mixture was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (40 mg, 0.637 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 0.5 hours, the solvent was removed, and the residue was separated by preparative chromatography column [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain 1 1 -methyl-4,5-((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (7.01 mg, yield: 43.2%). MS m / z (ESI): 513.2 [M+1] + .

[0439] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.35(s,1H),8.30(d,J=5.8Hz,1H),8.02(s,1H),7.93(s, 1H),6.76(d,J=5.8Hz,1H),5.63(d,J=9.9Hz,1H),4.72(q,J=8.9Hz,1H),4.51(t,J=10.8Hz,1H) ,4.30-4.21(m,1H),3.74(s,3H),2.71(s,1H),2.58(td,J=13.4,4.3Hz,3H),2.26(dd,J=14.3,1 0.3Hz, 1H), 2.16 (s, 5H), 1.87 (ddq, J=13.7, 7.0, 3.5Hz, 2H), 1.66 (dqd, J=16.1, 9.0, 3.3Hz, 2H).

[0440] Example 32: (S)-1 1 ,6-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0441] (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ylethynyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (35 mg, 0.079 mmol) was dissolved in methanol (3 mL), and aqueous formaldehyde solution (0.5 mL, 37% by mass) was added. The mixture was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (40 mg, 0.637 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 0.5 hours, the solvent was removed, and the residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain (S)-1 1 ,6-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (15.64 mg, yield: 41.2%). MS m / z (ESI): 459.6 [M+1] + .

[0442] 1 H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 8.31-8.20 (m, 2H), 7.90 (d, J = 2.3Hz, 2H), 6.73(d,J=5.8Hz,1H),5.21(d,J=7.4Hz,1H),4.50(td,J=9.1,3.7Hz,1H),4.29- 4.20(m,1H),4.00(d,J=6.3Hz,1H),3.77(s,3H),2.70(s,1H),2.59(s,2H),2.1 7(s,7H),1.93-1.83(m,2H),1.67(td,J=8.9,4.4Hz,2H),1.40(d,J=6.6Hz,3H).

[0443] Examples 33 to 67 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 31 or Example 32:

[0444] The NMR data of the compound prepared in the above example are as follows:

[0445] Example 69:1 1 ,5-dimethyl-45 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyridin-4(2,4)-pyrimidin-1(4,5)-pyrazoloheterocyclononane

[0446] 1 1 ,5-dimethyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyridin-4(2,4)-pyrimidin-1(4,5)-pyrazoloheterocyclononane (60 mg, 0.12 mmol) was dissolved in methanol (3 mL), and aqueous formaldehyde solution (1 mL, 37% mass fraction) was added. The mixture was stirred at room temperature for 30 minutes, and sodium cyanoborohydride (46 mg, 0.73 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 0.5 hours, the solvent was removed, and the residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain 1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyridin-4(2,4)-pyrimidin-1(4,5)-pyrazoloheterocyclononane (26 mg, yield: 42.14%). MS m / z (ESI): 527.6 [M+1] + .

[0447] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.72 (s, 1H), 8.31 (d, J = 5.8Hz, 1H), 8.11 (s,1H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.69(t,J=9.2Hz,1H),4.44(t,J=1 0.8Hz,1H),4.29(d,J=9.8Hz,1H),3.77(s,3H),3.13(s,3H),2.58(d,J=11.5Hz ,3H),2.39(d,J=13.1Hz,2H),2.17(s,5H),1.85(s,2H),1.62(q,J=9.5Hz,2H).

[0448] Examples 23, 70 to 89 can be prepared by selecting corresponding raw materials according to part or all of the synthesis method of Example 69:

[0449] The NMR data of the compound prepared in the above example are as follows:

[0450] Example 90: (S)-1-(4-((4-(1 1 ,6-dimethyl-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononan-5-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethan-1-one

[0451] (S)-1 1 ,6-dimethyl-5-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine (30 mg, 0.30 mmol) was added. After stirring at room temperature for 10 minutes, acetic anhydride (12.25 mg, 0.120 mmol) was added and the mixture was stirred at room temperature for 60 minutes. The solvent was removed and the residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to give (S)-1-(4-((4-(1 1 ,6-dimethyl-1 1 (H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononan-5-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethan-1-one (5.6 mg, yield: 16.6%). MS m / z (ESI): 543.6 [M+1] + .

[0452] 1H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.47(d,J=2.3Hz,1H),8.25(d,J=5.8Hz,1H),7.92(s,1H),7.82( s,1H),7.72(d,J=5.9Hz,1H),7.43(s,1H),6.75(d,J=5.8Hz,1H),5.82(dd,J=6.1,2.3Hz,1H),4.68-4 .51(m,2H),4.41-4.24(m,2H),4.04(d,J=7.2Hz,2H),3.83-3.77(m,4H),3.01(t,J=12.7Hz,1H),2.60 -2.55(m,1H),2.26-2.07(m,2H),1.98(s,3H),1.86(s,1H),1.50(t,J=15.3Hz,2H),1.26-0.96(m,5H).

[0453] Examples 91 to 109 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 90:

[0454] The NMR data of the compound prepared in the above example are as follows:

[0455] Example 110: (S)-1-(4-((1 1 ,6-dimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-(2,4)-pyridin-1(4,5)-pyrazolo[3-(2,4)-1-(4,5 ... 5 Preparation of 1-methyl)ethynyl)piperidin-1-yl)prop-2-en-1-one

[0456] Step 1: Synthesis of (S)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

[0457] (S)-Butane-1,3-diol (10.0 g, 110.9 mmol) was dissolved in dichloromethane (150 mL), and imidazole (8.3 g, 122.1 mmol) was added. A solution of tert-butyldimethylsilyl chloride (16.7 g, 111.0 mmol) in dichloromethane (50 mL) was added dropwise at room temperature. The reaction mixture was allowed to react at room temperature for 18 hours. After completion of the reaction, the mixture was diluted with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-12%:PE:EA] to obtain (S)-4-((tert-butyldimethylsilyl)oxy)butane-2-ol (18.2 g, yield: 80.2%).

[0458] Step 2: Synthesis of (S)-5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-chloropyridin-4-amine

[0459] 5-Bromo-2,4-dichloropyridine (5 g, 22.0 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of sodium hydride (0.56 g, 23.3 mmol), followed by the slow addition of (S)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (4.5 g, 22.0 mmol). The reaction mixture was heated to 25°C overnight. After completion of the reaction, as determined by LCMS, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated using a flash silica gel column [0-10%:ethyl acetate:petroleum ether] to afford (S)-5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-2-chloropyridine (2.9 g, yield: 33.3%). MS m / z(ESI):394.0 / 396.0[M+1] + .

[0460] Step 3: Synthesis of tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0461] Dissolve (S)-5-bromo-N-(4-((tert-butyldimethylsilyl)oxy)butan-2-yl)-2-chloropyridin-4-amine (2.5 g, 6.3 mmol) in N,N-dimethylformamide (10 mL). Add tert-butyl 4-ethynylpiperidine-1-carboxylate (4.0 g, 19.1 mmol), bis(triphenylphosphine)palladium dichloride (0.92 g, 1.3 mmol), and triethylamine (4 mL). Heat the reaction mixture to 80°C for 18 hours. After the reaction was complete, the reaction solution was concentrated by LCMS, and the residue was separated using a flash silica gel column [0-30% ethyl acetate:petroleum ether] to give tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (2.0 g, yield: 60.4%). MS m / z (ESI): 523.2 [M+1] + .

[0462] Step 4: Synthesis of tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0463] Tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (1.9 g, 3.6 mmol) was dissolved in dioxane (80 mL), and then 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (1.3 g, 4.0 mmol), cesium carbonate (3.0 g, 9.2 mmol), tris(dibenzylideneacetone)dipalladium (366 mg, 0.4 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (463 mg, 0.8 mmol) were added. The reaction liquid was replaced with nitrogen three times and heated to 115°C for 1 hour. After the reaction was completed, the solvent was removed and the residue was separated using a flash silica gel column [0-10% methanol:dichloromethane] to give tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (900 mg, yield: 30.7%). MS m / z (ESI): 808.4 [M+1] + .

[0464] Step 5: Synthesis of tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)oxy)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0465] Tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-6-((2-(2-methyl-3-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (900 mg, 1.1 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 mL, 2.0 mmol) was added, and the mixture was heated to 60° C. and stirred for 18 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated using a flash silica gel column [0-15%: dichloromethane: methanol] to provide tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)oxy)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (300 mg, yield: 47.8%). MS m / z (ESI): 564.8 [M+1] + .

[0466] Step 6: tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-(2,4)-pyridin-1(4,5)-pyrazolo[3-(2,4)-1-(4,5 ... 5 Synthesis of 1-methyl)ethynyl)piperidine-1-carboxylate

[0467] Tert-butyl (S)-4-((6-((2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-4-((4-hydroxybutan-2-yl)amino)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (300 mg, 0.53 mmol) was dissolved in toluene (10 mL) and cyanomethylenetri-n-butylphosphine (300 mg, 1.2 mmol) was added. The reaction solution was replaced with nitrogen three times and heated to 135°C for 18 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [0-10%: dichloromethane: methanol] to obtain tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-nitropropane 5 -yl)ethynyl)piperidine-1-carboxylate (120 mg, yield: 41.3%). MS m / z (ESI): 546.7 [M+1] + .

[0468] Step 7: (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ethynyl)-1 1 Synthesis of H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane

[0469] Tert-butyl (S)-4-((1 1 ,6-dimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-(2,4)-pyridin-1(4,5)-pyrazolo[3-(2,4)-1-(4,5 ... 5 -yl)ethynyl)piperidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), and a dioxane solution of hydrochloric acid (1 mL, 4 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain crude product (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ethynyl)-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane (80 mg, yield: 97.8%). MS m / z (ESI): 446.6 [M+1] + .

[0470] Step 8: (S)-1-(4-((11,6-dimethyl-11H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane-4-yl)- 5 Synthesis of 1-methyl)ethynyl)piperidin-1-yl)prop-2-en-1-one

[0471] (S)-1 1 ,6-dimethyl-4 5 -(piperidin-4-ethynyl)-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (80 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), and triethylamine (80 mg, 0.8 mmol) was added. The mixture was stirred at 0°C for 30 minutes, and then acryloyl chloride (16 mg, 0.17 mmol) was added to the mixture. The reaction solution was stirred at 0°C for 0.5 hours, and the solvent was removed. The residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to give (S)-1-(4-((1 1,6-dimethyl-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-(2,4)-pyridin-1(4,5)-pyrazolo[3-(2,4)-1-(4,5 ... 5 -yl)ethynyl)piperidin-1-yl)prop-2-en-1-one (10 mg, yield: 11.1%). MS m / z (ESI): 500.1 [M+1] + .

[0472] 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.73(s,1H),8.31(s,1H),8.19-8.03( s,1H),7.96-7.82(s,1H),6.87-6.69(m,2H),6.18-5.97(m,1H),5.67(d,J=1 0.4Hz,1H),4.94(m,1H),4.50(d,J=9.3Hz,1H),4.33(m,2H),3.76(s,3H),2. 27(s,2H),2.15(s,2H),1.98(s,2H),1.81(s,2H),1.58(s,2H),1.44(d,3H).

[0473] Example 111:5 1 -methyl-5 1 H-6-Oxa-3-aza-1(4,3)-morpholino-4(4,2)-pyrimidin-2(4,2)-pyridin-5(4,5)-pyrazoloheterocyclooctane-2 5 - Preparation of amines

[0474] 5 1 -methyl-2 5 -Nitro-5 1 H-6-oxa-3-aza-1(4,3)-morpholino-4(4,2)-pyrimidin-2(4,2)-pyridin-5(4,5))-pyrazoloheterocyclooctane (13 mg, 0.03 mmol) was dissolved in a mixed solution of methanol (3 mL) and tetrahydrofuran (0.5 mL), and 10% palladium carbon (16.50 mg, 0.02 mmol) was added and stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed by LCMS, the solvent was removed and the residue was separated by preparative chromatography column [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain 5 1 -methyl-5 1 H-6-Oxa-3-aza-1(4,3)-morpholino-4(4,2)-pyrimidin-2(4,2)-pyridin-5(4,5)-pyrazoloheterocyclooctane-2 5-amine (4 mg, yield: 33.11%). MS m / z (ESI): 395.4 [M+1] + .

[0475] 1 H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 8.16 (d, J = 5.8Hz, 1H), 7.91 (s, 1H), 7.84 ( s,1H),7.75(s,1H),6.58(d,J=5.8Hz,1H),4.75-4.60(m,3H),4.32-4.21(m,1H ),3.99(d,J=10.6Hz,1H),3.83-3.73(m,2H),3.70(s,3H),3.55-3.47(s,1H),3 .43-3.33(m,2H),3.12(d,J=12.3Hz,1H),1.90-1.80(m,1H),1.68-1.56(m,1H).

[0476] Example 112:1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0477] 1'-Methyl-5'-(piperidin-4-ylethynyl)spiro(cyclobutane-1,7'-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane) (32 mg, 0.064 mmol) was dissolved in methanol (3 mL), and triethylamine (0.33 mL, 2.38 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (29.80 mg, 0.13 mmol) were added. The reaction solution was heated at 80°C with stirring for 1 hour, and the solvent was removed. The residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain 1 1 -methyl-4 5 -((1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (17.7 mg, yield: 45.0%). MS m / z (ESI): 581.6 [M+1] + .

[0478] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.36(s,1H),8.30(d,J=5.8Hz,1H),8.02(s,1H),7.93(s,1H), 6.76(d,J=5.9Hz,1H),5.66(d,J=9.9Hz,1H),4.71(q,J=9.0Hz,1H),4.51(t,J=10.9Hz,1H),4.26(d, J=9.8Hz,1H),3.74(s,3H),3.16(q,J=10.2Hz,2H),2.89-2.81(m,2H),2.76(p,J=4.3Hz,1H),2.57(d d,J=20.9,10.4Hz,3H),2.33-2.22(m,1H),1.87(dd,J=6.9,3.6Hz,2H),1.68(tt,J=9.4,4.5Hz,2H).

[0479] Examples 113 to 122 can be prepared by selecting corresponding raw materials according to the synthesis method of Example 112:

[0480] The NMR data of the compound prepared in the above example are as follows:

[0481] Example 123:4 5 -((1-methoxypiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0482] 4 5 -Br-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (150 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 4-ethynyl-1-methoxypiperidine (150 mg, 1.078 mmol), cuprous iodide (118 mg, 0.619 mmol), cesium carbonate (444 mg, 1.363 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (225 mg, 0.248 mmol) and triethylamine (1 mL) were added. The reaction liquid was replaced with nitrogen three times and heated to 105°C for 6 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to obtain 4 5 -((1-methoxypiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (87 mg, yield: 52.14%). MS m / z (ESI): 543.6 [M+1] + .

[0483] 1 H NMR (400MHz, DMSO-d6) δ10.14 (s, 1H), 8.65 (s, 1H), 8.24 (d, J = 5.8Hz, 1H), 8.10-7. 99(m,1H),7.90(s,1H),6.73(d,J=5.8Hz,1H),4.72-4.54(m,1H),4.37(t,J=10.8Hz ,1H),4.27-4.15(m,1H),3.70(s,3H),3.35(s,3H),3.25-3.16(m,1H),3.10-2.85( m,4H),2.73-2.57(m,1H),2.54-2.46(m,1H),2.37-2.20(m,2H),2.01-1.40(m,5H).

[0484] Example 124: 2-(4-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 Preparation of acetonitrile

[0485] 1 1 ,5-dimethyl-4 5 -(piperidin-4-ylethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (50 mg, 0.098 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (40.45 mg, 0.293 mmol) and bromoacetonitrile (0.010 mL, 0.146 mmol) were added. The mixture was stirred at 80°C for 2 hours. After the reaction was completed, the solvent was removed. The residue was separated by preparative chromatography [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to give 2-(4-((1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane-4-oxa-3,5-diaza-2(2,4)-pyrimidin ... 5 -yl)ethynyl)piperidin-1-yl)acetonitrile (16.1 mg, yield: 28.4%). MS m / z (ESI): 552.6 [M+1] + .

[0486] 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8.12(s,1H),7.96(s,1H),6.80(d,J=5.8Hz, 1H),4.78-4.63(m,1H),4.44(t,J=10.8Hz,1H),4.29(d,J=9.3Hz,1H),3.77(s,3H),3.71(s,2H),3.13(s,3H),2.73(s, 3H), 2.56 (s, 1H), 2.37 (q, J = 9.6Hz, 4H), 1.90 (s, 2H), 1.65 (d, J = 9.2Hz, 2H).

[0487] Examples 125 and 126: (S)-1 1 -methyl-4 5 -(pyridin-2-yl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane and (R)-1 1 -methyl-4 5 -(pyridin-2-yl)-6-(trifluoromethyl)-11 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0488] 1 1 -methyl-4 5 -(pyridin-2-yl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was chirally resolved to give (S)-1 1 -methyl-4 5 -(pyridin-2-yl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane (150 mg, yield: 48.69%) and (R)-1 1 -methyl-4 5 -(pyridin-2-yl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane (142 mg, yield: 46.42%).

[0489] Separation conditions: instrument: UPCC (Waters), column: CHIRALPAK IK 4.6×100 mm, 3 μm (Daicel), column temperature: 40°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 55 / 45, flow rate: 3.0 mL / min, pressure: 2000 psi, injection volume: 5 μL.

[0490] Example 125: MS m / z (ESI): 469.6 [M+1] + .

[0491] 1H NMR(400MHz,DMSO-d6)δ10.51(d,J=9.0Hz,1H),10.10(s,1H),8.68(s,1H),8.62- 8.55(m,1H),8.38(s,1H),8.32(d,J=5.8Hz,1H),8.10(d,J=8.3Hz,1H),7.98-7.88 (m,2H),7.37-7.31(m,1H),6.81(d,J=5.8Hz,1H),4.79-4.70(m,1H),4.64(t,J=1 0.7Hz,1H),4.32-4.24(m,1H),3.75(s,3H),2.72-2.62(m,1H),2.19-2.10(m,1H).

[0492] Example 126: MS m / z (ESI): 469.6 [M+1] + .

[0493] 1 H NMR(400MHz,DMSO-d6)δ10.51(d,J=9.0Hz,1H),10.10(s,1H),8.68(s,1H),8.61- 8.55(m,1H),8.38(s,1H),8.32(d,J=5.8Hz,1H),8.10(d,J=8.3Hz,1H),7.98-7.87 (m,2H),7.38-7.31(m,1H),6.81(d,J=5.8Hz,1H),4.79-4.69(m,1H),4.64(t,J=1 0.8Hz,1H),4.33-4.25(m,1H),3.75(s,3H),2.73-2.61(m,1H),2.20-2.10(m,1H).

[0494] Examples 127 and 128: (R)-1 1 -methyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-1 1 -methyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0495] 11 -methyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was chirally resolved to give (R)-1 1 -methyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-11-methyl-45-((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-11H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane.

[0496] Separation conditions: instrument: UPCC (Waters), column: CHIRALPAK IK 4.6×100 mm, 3 μm (Daicel), column temperature: 40°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 55 / 45, flow rate: 3.0 mL / min, pressure: 2000 psi, injection volume: 7 μL.

[0497] Example 127: MS m / z (ESI): 513.6 [M+1] + .

[0498] 1H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.35(s,1H),8.30(d,J=5.8Hz,1H),8.02(s,1H) ,7.93(s,1H),6.76(d,J=5.8Hz,1H),5.63(d,J=9.8Hz,1H),4.72(q,J=9.0Hz,1H),4.51 (t,J=10.8Hz,1H),4.26(d,J=9.7Hz,1H),3.74(s,3H),2.71(s,1H),2.59(d,J=11.4Hz, 3H), 2.26 (dd, J=14.1, 10.5Hz, 1H), 2.16 (s, 5H), 1.92-1.80 (m, 2H), 1.74-1.59 (m, 2H).

[0499] Example 128: MS m / z (ESI): 513.6 [M+1] + .

[0500] 1H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.35(s,1H),8.30(d,J=5.8Hz,1H),8.02(s ,1H),7.93(s,1H),6.76(d,J=5.8Hz,1H),5.63(d,J=9.8Hz,1H),4.71(d,J=9.3Hz ,1H),4.51(t,J=10.9Hz,1H),4.26(d,J=9.6Hz,1H),3.74(s,3H),2.71(s,1H),2. 59 (d, J = 11.9 Hz, 2H), 2.26 (t, J = 12.3 Hz, 2H), 2.16 (s, 5H), 1.64 (d, J = 9.1 Hz, 2H).

[0501] Examples 129 and 130: (S)-4 5 -((2-ethyl-2-azaspiro[3.3]hept-6-yl)ethynyl)-1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (R)-4 5 -((2-ethyl-2-azaspiro[3.3]hept-6-yl)ethynyl)-1 1 -methyl-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0502] 4 5 -((2-ethyl-2-azaspiro[3.3]hept-6-yl)ethynyl)-1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was chirally resolved to give (S)-4 5 -((2-ethyl-2-azaspiro[3.3]hept-6-yl)ethynyl)-1 1 -methyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (R)-4 5 -((2-ethyl-2-azaspiro[3.3]hept-6-yl)ethynyl)-1 1 -methyl-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane.

[0503] Separation conditions: instrument: UPCC (Waters), column: (R,R)-WHELK-O1, 3.5um (Regis), column temperature: 40°C, mobile phase: CO2 / EtOH [1% NH3 (7M in MeOH)] = 55 / 45, flow rate: 3.0 mL / min, pressure: 2000 psi, injection volume: 7.5 μL.

[0504] Example 129: MS m / z (ESI): 539.6 [M+1] + .

[0505] 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.36–8.27(m,2H),8.00(s,1H),7.93(s,1H),6.75(d ,J=5.8Hz,1H),5.73(d,J=9.9Hz,1H),4.70(d,J=9.4Hz,1H),4.50(t,J=10.9Hz,1H),4.26( d,J=9.4Hz,1H),3.74(s,3H),3.29-3.14(m,1H),3.08(d,J=13.8Hz,4H),2.91(m,2H),2.62 -2.52(m,1H),2.48(s,3H),2.31(d,J=8.4Hz,2H),2.28-2.16(m,1H),0.83(t,J=7.2Hz,3H).

[0506] Example 130: MS m / z (ESI): 539.6 [M+1] + .

[0507] 1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.36-8.27(m,2H),8.00(s,1H),7.93(s,1H),6.75(d ,J=5.8Hz,1H),5.73(d,J=9.9Hz,1H),4.70(d,J=9.4Hz,1H),4.50(t,J=10.9Hz,1H),4.26( d,J=9.4Hz,1H),3.74(s,3H),3.29-3.14(m,1H),3.08(d,J=13.8Hz,4H),2.91(m,2H),2.62 -2.52(m,1H),2.48(s,3H),2.31(d,J=8.4Hz,2H),2.28-2.16(m,1H),0.83(t,J=7.2Hz,3H).

[0508] Examples 131 and 132: (R)-1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0509] 1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was chirally resolved to give (R)-1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-1 1 ,5-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-6-(trifluoromethyl)-1 1H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane.

[0510] Separation conditions: instrument: UPCC (Waters), column: CHIRALPAK OD 4.6×100 mm, 5 um (Daicel), column temperature: 40°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 75 / 25, flow rate: 3.0 mL / min, pressure: 2000 psi, injection volume: 5 μL.

[0511] Example 131: MS m / z (ESI): 527.6 [M+1] + .

[0512] 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8 .11(s,1H),7.96(s,1H),6.80(d,J=5.9Hz,1H),4.70(t,J=9.3Hz,1H),4.44 (t,J=10.8Hz,1H),4.29(d,J=9.6Hz,1H),3.77(s,3H),3.12(s,3H),2.78-2 .58(m,3H),2.50-2.30(m,2H),2.24(s,5H),1.87(s,2H),1.70-1.58(m,2H).

[0513] Example 132: MS m / z (ESI): 527.6 [M+1] + .

[0514] 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8 .11(s,1H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.70(t,J=9.2Hz,1H),4.44 (t,J=10.8Hz,1H),4.29(d,J=9.9Hz,1H),3.77(s,3H),3.13(s,3H),2.81-2 .53(m,3H),2.41-2.32(m,2H),2.20(s,5H),1.86(s,3H),1.70-1.62(m,2H).

[0515] Examples 133 and 134: (R)-4 5-((1-ethylpiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-4 5 -((1-ethylpiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0516] 4 5 -((1-ethylpiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was chirally resolved to give (R)-4 5 -((1-ethylpiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-4 5 -((1-ethylpiperidin-4-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane.

[0517] Separation conditions: instrument: SFC-9, column: CHIRALPAK IC 250×50 mm, 5 um (Daicel), mobile phase: CO 2 / [EtOH (0.1% NH 3 H 2 O)]=45 / 55, flow rate: 200 ml / min.

[0518] Example 133: MS m / z (ESI): 541.6 [M+1] + .

[0519] 1H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8.10(s ,1H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.68(q,J=9.3Hz,1H),4.44(t,J=10.8H z,1H),4.29(d,J=9.7Hz,1H),3.77(s,3H),3.13(s,3H),2.66(brs,3H),2.46-2.2 3(m,4H),2.15(brs,2H),1.85(brs,2H),1.68-1.55(m,2H),0.99(t,J=7.2Hz,3H).

[0520] Example 134: MS m / z (ESI): 541.6 [M+1] + .

[0521] 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.72(s,1H),8.31(d,J=5.8Hz,1H),8.10(s ,1H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.69(t,J=9.2Hz,1H),4.44(t,J=10.8H z,1H),4.29(d,J=9.9Hz,1H),3.77(s,3H),3.13(s,3H),2.67(brs,3H),2.45-2.2 3(m,4H),2.15(s,2H),1.91-1.78(m,2H),1.66-155m,2H),0.99(t,J=7.2Hz,3H).

[0522] Examples 135 and 136: (R)-4 5 -((2-ethyl-2-azaspiro[3.3]heptane-6-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-4 5 -((2-ethyl-2-azaspiro[3.3]heptane-6-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 Preparation of H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane

[0523] 4 5 -((2-ethyl-2-azaspiro[3.3]heptane-6-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane was separated by chiral separation to give (R)-4 5 -((2-ethyl-2-azaspiro[3.3]heptane-6-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidin-4(2,4)-pyridin-1(4,5)-pyrazoloheterocyclononane and (S)-4 5 -((2-ethyl-2-azaspiro[3.3]heptane-6-yl)ethynyl)-1 1 ,5-dimethyl-6-(trifluoromethyl)-1 1 H-9-oxa-3,5-diaza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane.

[0524] Separation conditions: instrument: SFC-5, column: (S,S)-WHELK-O1, 250mm*50mm, 10um (Regis), mobile phase: CO2 / [EtOH (0.1% NH3H2O)]=45 / 55, flow rate: 200ml / min.

[0525] Example 135: MS m / z (ESI): 553.6 [M+1] + .

[0526] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.71(s,1H),8.31(d,J=5.8Hz,1H),8.09(s,1H),7.96(s,1H),6.80(d,J=5.9Hz,1H),4.70(t,J=9.2Hz,1H ),4.44(t,J=10.8Hz,1H),4.29(d,J=10.0Hz,1H),3.77(s,3H),3.15-3. 00(m,8H),2.43-2.21(m,4H),2.18-2.06(m,2H),0.82(t,J=7.2Hz,3H).

[0527] Example 136: MS m / z (ESI): 553.6 [M+1] +.

[0528] 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.71(s,1H),8.31(d,J=5.8Hz,1H),8 .09(s,1H),7.96(s,1H),6.80(d,J=5.8Hz,1H),4.74-4.59(m,1H),4.44(t,J =10.8Hz,1H),4.29(d,J=9.9Hz,1H),3.77(s,3H),3.22-3.04(m,8H),2.47(d ,J=1.9Hz,1H),2.42-2.30(m,3H),2.22-2.12(m,2H),0.83(t,J=7.2Hz,3H).

[0529] Examples 137 to 152 were prepared by resolution of the corresponding racemates. The resolution or preparation conditions were as described in one of Examples 125 to 136.

[0530] The NMR data of the compound prepared in the above example are as follows:

[0531] Example 153: (S)-1 1 ,6-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-1 1 Preparation of H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane

[0532] Step 1: Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

[0533] (3R)-butane-1,3-diol (9.950 mL, 110.963 mmol) was added to CHCl (30 mL), followed by imidazole (8.31 g, 122.059 mmol) and TBSCl (16.72 g, 110.963 mmol). The reaction was stirred at 25°C overnight. After completion, the reaction solution was diluted with water and extracted three times with CHCl. ​​The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (14 g, 68.5 mmol, yield: 61.7%).

[0534] 1 H NMR (400MHz, CDCl3) δ4.07-3.95 (m, 1H), 3.89 (dt, J = 9.7, 4.7Hz, 1H), 3.80 (ddd, J = 10. 2,8.7,4.2Hz,1H),3.40(s,1H),1.74-1.55(m,2H),1.18(d,J=6.2Hz,3H),0.89(s,9H).

[0535] Step 2: Synthesis of 3,5-dibromo-2-chloropyridin-4-ol

[0536] 2-Chloropyridin-4-ol (20 g, 154.39 mmol) was added to acetic acid (100 mL), and Br2 (16.7 mL, 324.22 mmol) was added dropwise at 0°C. The reaction was stirred at 25°C overnight. After completion of the reaction, the reaction solution was poured into water and filtered to obtain crude 3,5-dibromo-2-chloropyridin-4-ol (38 g, 132.25 mmol, yield: 85.7%). The crude product was dried and used directly in the next reaction. MS m / z (ESI): 285.8 [M+1] + .

[0537] Step 3: Synthesis of 5-bromo-2-chloropyridin-4-ol

[0538] 3,5-Dibromo-2-chloropyridin-4-ol (24 g, 83.528 mmol) was added to THF (240 mL). Under a nitrogen atmosphere, the mixture was cooled to -78°C, and n-BuLi (63.48 mL, 158.70 mmol) was added dropwise. The reaction temperature was maintained for 30 minutes. After completion of the reaction, the reaction solution was quenched with water, the pH was adjusted to 4-5 with 2N hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain 5-bromo-2-chloropyridin-4-ol (8.71 g, 41.76 mmol, yield: 50%). MS m / z (ESI): 207.8 [M+1] + .

[0539] 1 H NMR (400MHz, DMSO-d6) δ12.34(s,1H),8.41(s,1H),6.98(s,1H).

[0540] Step 4: Synthesis of (S)-5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-2-chloropyridine

[0541] Dissolve 5-bromo-2-chloropyridin-4-ol (1.2 g, 5.757 mmol) and (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (1.41 g, 6.908 mmol) in THF (50 mL), then add Ph3P (2.27 g, 8.636 mmol). Under a nitrogen atmosphere, cool to 0°C, and add diisopropyl azodicarboxylate (1.370 mL, 6.908 mmol) dropwise. After complete addition, react at 50°C for 4 hours. After completion of the reaction, dilute the reaction solution with brine and extract with ethyl acetate. The crude product is diluted with water and extracted three times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue was separated by silica gel column chromatography to give (S)-5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-2-chloropyridine (1.73 g, 4.382 mmol, yield: 76.1%). MS m / z (ESI): 394.2 [M+1] + .

[0542] Step 5: Synthesis of tert-butyl (S)-4-((4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0543] Tert-butyl 4-ethynylpiperidine-1-carboxylate (1.5 g, 7.17 mmol) and (S)-5-bromo-4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-2-chloropyridine (1.98 g, 5.02 mmol) were dissolved in triethylamine (20 mL), and Pd(dppf)Cl2 (0.52 g, 0.72 mmol) and CuI (0.27 g, 1.433 mmol) were added. The mixture was heated at 50°C with stirring under nitrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was separated by silica gel column chromatography to give (S)-tert-butyl 4-((4-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (2.07 g, 3.97 mmol, yield: 55.2%).

[0544] Step 6: Synthesis of (S)-3-((2-chloro-5-(piperidin-4-ylethynyl)pyridin-4-yl)oxy)butan-1-ol

[0545] Tert-butyl (S)-4-((4-((4-((tert-Butyldimethylsilyl)oxy)but-2-yl)oxy)-6-chloropyridin-3-yl)ethynyl)piperidine-1-carboxylate (2.07 g, 3.96 mmol) was dissolved in CHCl (20 mL), TFA (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, diluted with CHCl (20 mL), KCO (2.19 g, 15.82 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The mixture was filtered, the filtrate was concentrated, and the residue was separated by normal phase column chromatography to give (S)-3-((2-chloro-5-(piperidin-4-ylethynyl)pyridin-4-yl)oxy)butan-1-ol (950 mg, 3.07 mmol, yield: 77.7%). MS m / z (ESI): 309.2 [M+1] + .

[0546] Step 7: Synthesis of (S)-3-((2-chloro-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yl)oxy)butane-1-ol

[0547] (S)-3-((2-chloro-5-(piperidin-4-ylethynyl)pyridin-4-yl)oxy)butan-1-ol (850 mg, 2.75 mmol) was dissolved in MeOH (20 mL). Formaldehyde (268 mg, 30% aqueous solution), HOAc (0.008 mL, 0.138 mmol), and NaBH(OAc)3 (870.9 mg, 4.13 mmol) were added at 0°C and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH ~8 with saturated aqueous sodium bicarbonate. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography to give (S)-3-((2-chloro-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yl)oxy)butan-1-ol (630 mg, 322.8 mmol, yield: 70.9%). MS m / z (ESI): 323.2 [M+1] + .

[0548] Step 8: Synthesis of (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidin-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one

[0549] (S)-3-((2-chloro-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yl)oxy)butan-1-ol (500 mg, 1.549 mmol) and 4-(4-aminopyrimidin-2-yl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (498 mg, 1.549 mmol) were added to 1,4-dioxane (10 mL), followed by Cs2CO3 (1514 mg, 4.646 mmol), xantphos (269 mg, 0.465 mmol) and Pd2(dba)3 (213 mg, 0.232 mmol), and the reaction was heated in a microwave at 130°C under a nitrogen atmosphere for 2 hours. The reaction was completed and concentrated. The residue was separated by reverse phase column chromatography to give (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidine-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (520 mg).

[0550] Step 9: Synthesis of (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one

[0551] (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidin-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (520 mg, 0.856 mmol) was dissolved in THF (15 mL), and TBAF (0.757 mL, 2.567 mmol) and heated at 70°C for 2 hours. After the reaction was complete, the product was concentrated and the residue was separated by reverse phase column chromatography to give (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one (60 mg, 0.126 mmol, two-step yield: 8%). MS m / z (ESI): 478.2 [M+1] + .

[0552] Step 10: (S)-1 1 ,6-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-1 1 Synthesis of H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane

[0553] (S)-4-(4-((4-((4-hydroxybutan-2-yl)oxy)-5-((1-methylpiperidin-4-yl)ethynyl)pyridin-2-yl)amino)pyrimidin-2-yl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one (50 mg, 0.105 mmol) was dissolved in toluene (3 mL), and then CMBP (126.4 mg, 0.523 mmol) was added and heated at 130°C for 18 hours. After the reaction was complete, the mixture was concentrated and the residue was separated by preparative HPLC [acetonitrile / water (5% ammonium bicarbonate): 0-95%] to give (S)-1 1 ,6-dimethyl-4 5 -((1-methylpiperidin-4-yl)ethynyl)-1 1 H-5,9-dioxa-3-aza-2(2,4)-pyrimidinyl-4(2,4)-pyridinyl-1(4,5)-pyrazoloheterocyclononane (17.2 mg, 0.034 mmol, yield: 31.8%). MS m / z (ESI): 460.1 [M+1] + .

[0554] 1H NMR(400MHz,MeOH-d4)δ8.77(s,1H),8.26(d,J=6.0Hz,1H),8.09(s,1H),8.03 (s,1H),6.69(d,J=6.0Hz,1H),5.12-5.08(m,1H),4.71-4.66(m,1H),4.27-4. 22(m,1H),3.81(s,3H),3.13-3.05(m,2H),2.93-2.72(m,3H),2.58(s,3H),2. 33-2.29(m,2H),2.10-2.04(m,2H),1.90-1.80(m,2H),1.54(d,J=6.4Hz,3H).

[0555] Examples 154-165 and comparative compound 2 can be prepared by selecting corresponding raw materials according to all or part of the synthesis method of Example 153:

[0556] The NMR data of the compound prepared in the above example are as follows:

[0557] Biological test evaluation

[0558] (Cell proliferation assay)

[0559] (1) Reagents and consumables

[0560] DMEM medium (Gibco, Cat#11965118)

[0561] RPMI1640 culture medium (Gibco, Cat#11875119)

[0562] Fetal bovine serum (FBS) (GBICO, Cat#10099-141)

[0563] Luminescent cell viability assay kit (Promega, Cat#G7572)

[0564] Black transparent flat bottom 96-well plate ( Cat#3603)

[0565] (2) Instruments

[0566] SpectraMax Multilabel Microplate Reader MD, 2104-0010A;

[0567] CO2 incubator, Thermo Scientific 3100 series;

[0568] Biological safety cabinet, Thermo Scientific, 1300 series model A2;

[0569] Inverted microscope, Olympus, CKX41SF;

[0570] Siemens refrigerator, KK25E76TI.

[0571] (III) Cell lines and culture conditions

[0572] (IV) Experimental steps

[0573] 1. Cell culture and inoculation

[0574] (1) Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. Detect cell viability by trypan blue exclusion to ensure that the cell viability is above 90%.

[0575] (2) Adjust the cell concentration to achieve the desired final density; add 90 μL of cell suspension to a 96-well plate.

[0576] (3) The cells were incubated in a 96-well plate at 37°C, 5% CO2 and 95% humidity overnight.

[0577] 2. T0 benchmark data

[0578] (1) Add 10 μL of PBS to each well of the T0 plate containing cells.

[0579] (2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0580] (3) Add an equal volume of CTG solution to each well.

[0581] (4) Shake on an orbital shaker for 5 minutes to lyse the cells.

[0582] (5) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0583] (6) Read the T0 fluorescence signal value.

[0584] 3. Compound dilution and addition

[0585] (1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10 mM stock solution.

[0586] (2) Prepare 1000-fold and 3.16-fold diluted compound solutions.

[0587] (3) The 1000× diluted compound solution was diluted 100-fold with PBS to prepare a 10-fold compound solution. The highest concentration was 10 μM. Nine concentrations were diluted 3.16-fold. 10 μL of the drug solution was added to each well of a 96-well plate and the cells were inoculated. Three replicate wells were set for each compound concentration. The final DMSO concentration was 0.1%.

[0588] (4) The cells were placed in a 96-well plate containing drugs at 37°C, 5% CO2 and 95% humidity for 72 hours before CTG analysis.

[0589] 4. Fluorescence signal reading

[0590] (1) Thaw CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0591] (2) Add an equal volume of CTG solution to each well.

[0592] (3) Shake on an orbital shaker for 5 minutes to lyse the cells.

[0593] (4) Place the cell plate at room temperature for 20 minutes to stabilize the fluorescent signal.

[0594] (5) Read the fluorescence value.

[0595] 5. Data processing

[0596] The data were analyzed using GraphPad Prism 7.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curves, from which the IC was calculated. 50 The specific experimental results are shown in Table 1.

[0597] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0598] Table 1: Biological test results

[0599] Based on the biological activity data of the compounds in the specific examples, the compounds of the present invention have strong inhibitory effects on EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation, and Del19 / T790M / C797S triple mutation at the cellular level, and have high selectivity for EGFR WT. Under the same test conditions, compared with the control compounds, the compounds of the present invention have significantly improved inhibitory activity against EGFR mutations and selectivity for EGFR WT, with some compounds showing inhibitory activity increased by several dozen times and selectivity increased by more than ten times.

[0600] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above disclosure, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, X is NR9 or O; L is a bond or -C≡C-; R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, amino, C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 AND-OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, hydroxyl, =O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl and -NR 16 R 17 substituted by a substituent; R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 1-10 Alkylene, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 Substituents, provided that when R 3a and R 3b One of them is selected from C 1-10 when alkylene, the other is absent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaromatic Base, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; R6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 ; Each R7 and each R8 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 ; R9 is selected from hydrogen, deuterium, cyano, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-10 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl substituted C 1-10 Alkyl, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group substituted C 1-10 alkyl, C 6-10 Aryl, C 6-10 Aryl substituted C 1-10 Alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted C 1-10 Alkyl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR 10 )R 11 , -C 0-8 Alkyl-N=S(O)R 11 R 12 , -C 0-8 Alkyl-N=SR 11 R 12 , -C 0-8 Alkyl-OS(O)2R 13 , -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)SR 14 , -C 0-8 Alkyl-SC(O)R 15 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-P(O)(R 15 2. -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; Each R 10 are each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 and -C 0-8 Alkyl-C(O)NR 16 R 17 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, or, R 11 and R 12 Together with the sulfur atom directly connected thereto, a 3-10 membered heterocyclic group is formed, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 Alkyl-S(O) r R 13 , -C 0-8 Alkyl-OR 14 , -C 0-8 Alkyl-C(O)OR 14 , -C 0-8 Alkyl-C(O)R 15 , -C 0-8 Alkyl-OC(O)R 15 , -C 0-8 Alkyl-NR 16 R 17 , -C 0-8 Alkyl-C(=NR 16 )R 15 , -C 0-8 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-8 Alkyl-C(O)NR 16 R 17 and -C 0-8 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; Each R 13 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 14 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 15 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, 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 heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent; Or, R 16 and R 17 The nitrogen atom directly connected thereto forms a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, 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 heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent; m and n are each independently 0, 1 or 2; Each r is independently 0, 1 or 2.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxyl; R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 Substituents, provided that when R 3a and R 3b One of them is selected from C 1-4 when alkylene, the other is absent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 alkyl -N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 ; Each R7 and each R8 are independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 alkyl -N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 ; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR 10 )R 11 , -C 0-4 Alkyl-N=S(O)R 11 R 12 , -C 0-4 Alkyl-N=SR 11 R 12 , -C 0-4 Alkyl-OS(O)2R 13 , -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)SR 14 , -C 0-4 Alkyl-SC(O)R 15 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-P(O)(R 15 2. -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; Among them, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 1.

3. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Each R 10 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 and -C 0-4 Alkyl-C(O)NR 16 R 17 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; Each R 11 and R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 11 and R 12 and The directly connected sulfur atoms together form a 3-6 membered heterocyclic group, the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-S(O) r R 13 , -C 0-4 Alkyl-OR 14 , -C 0-4 Alkyl-C(O)OR 14 , -C 0-4 Alkyl-C(O)R 15 , -C 0-4 Alkyl-OC(O)R 15 , -C 0-4 Alkyl-NR 16 R 17 , -C 0-4 Alkyl-C(=NR 16 )R 15 , -C 0-4 Alkyl-N(R 16 )-C(=NR 17 )R 15 , -C 0-4 Alkyl-C(O)NR 16 R 17 and -C 0-4 Alkyl-N(R 16 )-C(O)R 15 substituted by a substituent; Each R 13 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, hydroxyl, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 14 independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 15 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 16 R 17 substituted by a substituent; Each R 16 and R 17 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, 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 substituted with an alkanoyl substituent; Or, R 16 and R 17 Together with the nitrogen atom directly connected thereto, a 4-8 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, 2C 1-4 Alkylamino and C 1-4 substituted with an alkanoyl substituent; Each r is independently 0, 1 or 2.

4. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIa): Wherein, X is NR9 or O; R1 is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxyl; R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen Generation C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 Substituents, provided that when R 3a and R 3b One of them is selected from C 1-4 when alkylene, the other is absent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 , -N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; Among them, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 1.

5. The compound of formula (I) according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl; The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of the aryl and 5-8 membered heteroaryl groups are selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 substituted by a substituent; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 alkyl, Deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 ; Among them, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 4.

6. The compound of formula (I) according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIIa): Wherein, X is NR9 or O; R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-10 Alkylene, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, halogen substituted C 1-10 Alkylene, deuterium substituted C 1-10 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, wherein the heteroatom of the heterocyclic group or heteroaryl group is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 substituted by a substituent; If the heterocyclic group or heteroaryl group in the above definition of substituent does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur; Among them, R1, R2, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 4.

7. The compound of formula (I) according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is a compound of formula (IVa1): Wherein, X is NR9 or O; R 1a Selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl; The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of the aryl and 5-8 membered heteroaryl groups are selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl; R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, halogen substituted C 1-4 Alkyl, Deuterium Replace C 1-4 Alkyl, halogen substituted C 1-4 Alkylene, deuterium substituted C 1-4 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, wherein the heteroatom of the heterocyclic group and the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; If the heterocyclic group or heteroaryl group in the above definition of substituent does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur; Among them, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 6.

8. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1a Selected from substituted C 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl; The C 1-4 The substituents of the alkyl group are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; The C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The substituents of the aryl and 5-8 membered heteroaryl groups are selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, wherein the heteroatom of the heterocyclic group and the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; If the heterocyclic group or heteroaryl group in the above definition of substituent does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur; Among them, R 13 , R 14 , R 15 , R 16 and R 17 As described in claim 7.

9. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: X is NR9; R9 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl and trideuteriomethyl.

10. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: X is O.

11. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is methyl.

12. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 3a is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethylene, difluoromethylene, cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetanyl, oxolanyl, aziridine, azetidinyl and aziridine.

13. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1a Selected from the following groups: 1) Substituted C 1-4 Alkyl, the C 1-4 The alkyl group is selected from methyl, ethyl, propyl and isopropyl, and the substituents of the methyl, ethyl, propyl and isopropyl groups are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; 2) Substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[3.4]octyl, Oxypropyl, oxetanyl, oxolyl, oxhexyl, aziridine, azetidinyl, aziridine, azohexyl, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, phenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyridinyl and pyrimidinyl, the above-mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, spiro[3.4]octyl, Oxypropyl, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, aziridine, azidene, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.4]octanyl, The substituents of phenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyridinyl and pyrimidinyl are selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Among them, R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 7.

14. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1a Selected from the following groups: 1) Substituted C 1-4 Alkyl, the C 1-4 The alkyl group is selected from methyl, ethyl, propyl and isopropyl, and the substituents of the methyl, ethyl, propyl and isopropyl groups are selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; 2) Substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 Aryl and substituted or unsubstituted 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 The aryl and 5-8 membered heteroaryl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, The above cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, The substituent is selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Among them, R 14 , R 15 , R 16 and R 17 As described in claim 7.

15. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1a Select one or more R 18a Substituted methyl, 1 or more R 18a Substituted ethyl, 1 or more R 18a Substituted propyl, 1 or more R 18a Substituted isopropyl, Each R 18a are each independently selected from halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl and -OR 14 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; Each R 18b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Each R 18c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Each R 18d are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Each R 18e are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Each R 18f are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, methylsulfonyl, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 ; Among them, R 14 , R 15 , R 16 and R 17 As described in claim 7.

16. The compound of formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1a Select one or more R 18a Substituted methyl, Each R 18a each independently selected from fluoro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxhexyl, aziridine, azetidinyl, aziridine, azohexyl, piperazinyl, morpholinyl, 2-azaspiro [3.3] heptane and hydroxy, the above groups are independently optionally further substituted by one or more selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, propyl, isopropyl substituted with a substituent selected from the group consisting of 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]hept ... Each R 18b are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, cyano-substituted methyl, cyano-substituted ethyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, -OR 14a 、-OC(O)R 15a and-NR 16a R 17a ; Each R 18c are each independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuterioethyl, dideuterioethyl, trideuterioethyl, methyl substituted with cyano, ethyl substituted with cyano, methyl substituted with hydroxy, ethyl substituted with hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolyl, oxhexyl, aziridine, azetidinyl, aziridine, azohexyl, piperazinyl, morpholinyl, 2-azaspiro[3.3]heptyl, methylsulfonyl, -OR 14a 、-C(O)OR 14a and -C(O)R 15a ; Each R 18d are each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, methyl substituted with cyano, methyl substituted with hydroxy, -OR 14a 、-OC(O)R 15a and-NR 16a R 17a ; Each R 18e each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, cyano-substituted methyl and hydroxy-substituted methyl; Each R 18f are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, cyano-substituted methyl, cyano-substituted ethyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, -OR 14a 、-OC(O)R 15a and-NR 16a R 17a ; Each R 14a are each independently hydrogen, methyl, trifluoromethyl or trideuteriomethyl; Each R 15a are each independently vinyl, methyl, ethyl, isopropyl or trifluoromethyl; Each R 16a are each independently hydrogen or methyl; Each R 17a are each independently hydrogen or methyl.

17. The compound of formula (I) according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IVa2): Among them, R 1b Selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, wherein the heteroatom of the heterocyclic group and the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Substituted by cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, -SF5, hydroxyl, amino, methylamino, dimethylamino substituents; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl; R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen, oxygen or sulfur, and the above C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 The group may be substituted by a cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclic oxy group, -SF5, a hydroxyl group, an amino group, a methylamino group, or a dimethylamino group.

18. The compound of formula (I) according to claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1b is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolyl, oxacyclohexyl, azetyl and azacyclohexyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino; R 4a and R 4b Together with the carbon atom directly attached thereto, it forms a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl group, which groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino.

19. The compound of formula (I) according to claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is methyl.

20. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIb): Wherein, X is NR9 or O; R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, Halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and hydroxyl; R 3a and R 3b are each independently selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 Substituents, provided that when R 3a and R 3b One of them is selected from C 1-4 when alkylene, the other is absent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 4a and R 4b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、 -O-S(O)2R 13 、 -S(O) r R 13 、 -O-R 14 、 -C(O)OR 14 、 -C(O)SR 14 、 -S-C(O)R 15 、 -C(O)R 15 、 -O-C(O)R 15 、 -P(O)(R 15 )2、 -NR 16 R 17 、 -C(=NR 16 )R 15 、 -N(R 16 )-C(=NR 17 )R 15 、 -C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 , or, R 5a and R 5b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; R6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 ; R9 is selected from hydrogen, deuterium, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-8 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, C 6-8 Aryl, C 6-8 Aryl substituted C 1-4 Alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted C 1-4 Alkyl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 、-NR 16 R 17 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; Provided that, when R9 is selected from hydrogen or C 1-4 When alkyl, R 3a , R 3b , R 4a , R 4b , R 5a and R 5b At least one of them is selected from deuterium, fluorine substituted C 1-4 Alkyl or deuterium substituted C 1-4 Alkyl, or R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen Generation C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=NR 10 )R 11 、-N=S(O)R 11 R 12 、-N=SR 11 R 12 、-OS(O)2R 13 、-S(O) r R 13 、-OR 14 、-C(O)OR 14 、-C(O)SR 14 、-SC(O)R 15 、-C(O)R 15 、-OC(O)R 15 、-P(O)(R 15 )2.-NR 16 R 17 、-C(=NR 16 )R 15 、-N(R 16 )-C(=NR 17 )R 15 、-C(O)NR 16 R 17 and -N(R 16 )-C(O)R 15 substituted by a substituent; Among them, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r as described in claim 1.

21. The compound of formula (I) according to claim 20, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; R 4a and R 4b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 ; R 5a and R 5b are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -SF5, -OR 14 and-NR 16 R 17 ; Among them, R 14 , R 15 , R 16 and R 17 As described in claim 20.

22. The compound of formula (I) according to claim 20, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIIb1): Among them, R 1c Selected from hydrogen, deuterium, halogen, cyano, nitro, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl; R 3a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene, fluorine substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, fluorine substituted C 1-4 Alkylene, deuterium substituted C 1-4 Alkylene, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; R9 is selected from deuterium, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, or, R9 and R 3a and the directly connected part together form a 4-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group or heteroaryl group is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, =O, =S, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; If the heterocyclic group or heteroaryl group in the above definition of substituent does not limit the heteroatom, the heteroatom is selected from nitrogen, oxygen or sulfur; Among them, R 14 , R 15 , R 16 and R 17 As described in claim 20.

23. The compound of formula (I) according to claim 22, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R9 is selected from deuterium, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, or R9 and R 3a and the directly connected part together form a 4-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen or oxygen, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted C 1-4 Alkyl, =O and -OR 14 The above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -OR 14 、-C(O)OR 14 、-C(O)R 15 、-OC(O)R 15 and-NR 16 R 17 substituted by a substituent; Among them, R 14 , R 15 , R 16 and R 17 As described in claim 22.

24. The compound of formula (I) according to claim 22, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1c is selected from hydrogen, nitro, amino, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently substituted with one or more substituents selected from fluorine, chlorine, cyano, methyl, ethyl, propyl and isopropyl; R2 is methyl; R 3a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monofluoromethylene and difluoromethylene; R9 is selected from cyano, cyclopropyl, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, or R9 and R 3a and the directly connected part together form a 6-membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen or oxygen, and the above groups are independently optionally further substituted by a or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and The above groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl and acetyl.

25. The compound of formula (I) according to claim 20, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIIb2): Among them, R 1d phenyl or 5-6 membered heteroaryl, wherein the heteroatom of the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 substituted by alkoxy, amino, methylamino and dimethylamino substituents; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl; R 3a is fluorine-substituted methyl or fluorine-substituted methylene; R 5a and R 5b are each independently hydrogen or deuterium.

26. The compound of formula (I) according to claim 25, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1d phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, wherein the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 The alkylene group may be substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, or an amino group.

27. The compound of formula (I) according to claim 25, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1d is selected from phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, and the above groups are independently optionally further substituted by one or more substituents selected from fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteriomethyl, dideuteriomethyl and trideuteriomethyl; R2 is methyl; R 3a is monofluoromethyl, difluoromethyl, trifluoromethyl or monofluoromethylene; R 5a and R 5b are each independently hydrogen or deuterium.

28. The compound of formula (I) according to claim 20, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) is the compound of formula (IIIb3): Among them, R 1e Selected from hydrogen, deuterium, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 aryl and 5-8 membered heteroaryl, wherein the heteroatom of the heterocyclic group and the heteroaryl is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 substituted by alkoxy, amino, methylamino and dimethylamino substituents; R2 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and hydroxyl; R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from nitrogen, oxygen or sulfur, and the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 The group may be substituted by a cycloalkoxy group, a 3-6 membered heterocyclic group, a 3-6 membered heterocyclic oxy group, -SF5, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group.

29. The compound of formula (I) according to claim 28, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1e is selected from hydrogen, deuterium, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino; R 3a and R 3b Together with the carbon atom directly attached thereto, it forms a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl group, which groups are independently optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino.

30. The compound of formula (I) according to claim 28, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1e is selected from hydrogen, phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, each of which is independently and optionally further substituted with one or more substituents selected from fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethoxy, trideuteromethoxy, hydroxyl and amino; R2 is methyl; R 3a and R 3b Together with the carbon atom to which it is directly attached, it forms a cyclopropyl group, which is optionally further substituted by one or more fluorine groups.

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

32. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

33. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 31, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

34. Use of a compound of formula (I) according to any one of claims 1 to 31, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, tumor or metastatic disease at least partially associated with EGFR Del19 mutation, EGFR L858R mutation, EGFR L858R / C797S double mutation, EGFR Del19 / C797S double mutation, L858R / T790M / C797S triple mutation and Del19 / T790M / C797S triple mutation.

35. Use of a compound of formula (I) according to any one of claims 1 to 31, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, cancers and / or metastatic diseases caused by excessive proliferation and induction of cell death disorders.

36. Use of a compound of formula (I) according to any one of claims 1 to 31, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma at least in part.

37. A compound of formula (I) according to any one of claims 1 to 31, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma at least in part.

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