Nitrogen-containing heterocyclic derivative inhibitors, their preparation method and application

Abstract

The present invention relates to a nitrogen-containing heterocyclic derivative inhibitor, its preparation method, and application thereof, specifically, a compound represented by general formula (I), its preparation method, a pharmaceutical composition containing the compound, and its use as an inhibitor in the treatment of cardiovascular and cerebrovascular diseases, etc., wherein each substituent in general formula (I) is as defined in the specification. [Formula 1] TIFF2025534174000172.tif47170

Description

[Technical Field]

[0001] This application is filed on October 14, 2022, Chinese Patent Application No. 2022112625520, filed on February 6, 2023, Chinese Patent Application No. 2023100954447, filed on February 14, 2023, Chinese Patent Application No. 2023101156001, filed on March 20, 2023, Chinese Patent Application No. 2023102752651, filed on March 30, 2023, This application claims priority to Chinese Patent Application No. 2023103333265, Chinese Patent Application No. 2023104650154 filed on April 26, 2023, Chinese Patent Application No. 2023106311997 filed on May 30, 2023, Chinese Patent Application No. 2023108187585 filed on July 4, 2023, and Chinese Patent Application No. 2023110111090 filed on August 10, 2023. This application references all of the above Chinese patent applications.

[0002] The present invention belongs to the field of drug synthesis, and specifically relates to nitrogen-containing heterocyclic derivative inhibitors and their preparation methods and applications. [Background technology]

[0003] Cardiovascular disease (CVD) is a leading cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. Accumulation of LDL-C in arterial walls can lead to atherosclerosis and potentially inflammatory responses, resulting in cardiovascular events such as heart attacks and strokes. Statins can reduce serum LDL-C and are currently the primary lipid-lowering medications used clinically. However, patients who are intolerant to statins or who fail to achieve treatment goals when treated with tolerated doses, such as those with familial hypercholesterolemia, remain at risk. The discovery of PCSK9 inhibitors offers a more aggressive treatment approach for both homozygous and heterozygous familial hypercholesterolemia patients. While the combination of the non-statin ezetimibe with a statin can reduce LDL-C by 15%–20%, the combination of a PCSK9 inhibitor with a statin can significantly reduce LDL-C by 54%–74%. PCSK9 inhibitors can also overcome intolerable side effects of statin drugs, such as muscle pain.

[0004] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease highly expressed in the liver. Loss-of-function mutations in the PCSK9 gene are associated with lower LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), making it a clinically validated target for the treatment of hyperlipidemia. PCSK9 is synthesized as a proenzyme, which undergoes autocatalytic cleavage within the cell after synthesis, resulting in the secretion of mature PCSK9 via the propeptide bond, which blocks the catalytic activity of PCSK9.

[0005] PCSK9 is a major modulator of hepatocyte surface low-density lipoprotein receptor (LDLR) levels and can inhibit the LDLR cycling pathway. LDLR function is important for maintaining cholesterol homeostasis and is responsible for the uptake and degradation of low-density lipoproteins. Circulating LDL binds to the N-terminal ligand-binding domain of the LDLR via apolipoprotein B100, and the LDL / LDLR complex is internalized by receptor-mediated endocytosis. The intracellular low pH environment releases LDL from the LDLR, which then cycles back to the plasma membrane. The intracellular free LDL is then delivered to lysosomes for degradation. Secreted PCSK9 contributes to the LDLR's cycling ability by binding to the hepatocyte surface LDLR. After the PCSK9 / LDLR complex translocates through a threoprotein-encapsulated cavity to an acidic endosomal compartment, a conformational change in the LDLR results in the formation of additional binding sites for PCSK9. Therefore, PCSK9 upregulates LDL-C levels by disrupting LDLR cycling, accompanied by lysosomal degradation of the LDLR. Summary of the Invention [Problem to be solved by the invention]

[0006] Familial hypercholesterolemia (FH) is a genetic disorder of low-density lipoprotein cholesterol metabolism, affecting 1 in 250 people. It is characterized by significantly elevated LDL-c levels. Patients with heterozygous FH have a 3-4 times higher risk of developing coronary heart disease (CAD) than healthy controls, and CAD often occurs an average of 10 years earlier than healthy controls. Statins reduce low-density lipoprotein cholesterol in patients with heterozygous FH. A study by Baselin found that high-intensity statin therapy can reduce the risk and mortality rate of coronary heart disease by 44%. However, in many cases, LDL-c reduction is insufficient. The counter-compensatory mechanism of statins is to upregulate sterol regulatory element-binding protein 2 (SREBP-2), thereby activating the LDL receptor and PCSK9, increasing PCSK9 expression and secretory binding to the LDLR, resulting in elevated blood LDL-c levels. Therefore, although statins reduce LDL by inhibiting HMG-CoA, they exert a counterbalancing effect on the action of SREPB, and adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatment routes, such as PCSK9 inhibitors, are necessary.

[0007] Alirocumab and Evolocumab, large molecule PCSK9 inhibitors based on monoclonal antibodies, selectively bind to extracellular PCSK9, blocking its interaction with LDLR, and are FDA-approved to reduce LDL-C levels, with favorable safety profiles. Studies have shown that in heterozygous FH patients who have not achieved LDL-C targets after treatment with statins alone, a single injection of Alirocumab every two weeks significantly reduces cardiovascular risk. Alirocumab has also been shown to moderately increase "good" cholesterol (HDL-C). In addition, the PCSK9 siRNA drug Inclisiran is currently on the market, which can reduce PCSK9 protein expression levels for long-term lipid lowering with favorable safety profiles. However, both of these drugs require injections, have high production costs, and are expensive. To date, no small molecule PCSK9 inhibitors have been commercially available, so there is a high demand for orally administered PCSK9 small molecule inhibitors.

[0008] PCSK9 small molecule inhibitors have been reported in patent documents such as WO 2014 / 170786 (Pfizer), WO 2014 / 150326 (Shifa), WO 2020 / 150473 (AZ), and WO 2022 / 133529 (Nyrada), with AZD-0780 currently in Phase I clinical trials and the others in preclinical development. Several polypeptides have also been reported, with the most advanced being in Phase II clinical trials. The present invention provides a need for the development of an orally administrable PCSK9 small molecule inhibitor. [Means for solving the problem]

[0009] An object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] where: Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and is preferably a 5-membered monoheteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and is preferably C 3-6 a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, C 3-6 a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, it is a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group or a 6-membered fused 6-membered bicyclic heteroaryl group, Ring A is preferably a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group, and Ring A is preferably a 6-membered monoheteroaryl group. [ka] When the formula is [ka] and wherein ring A is a 6-membered monoheteroaryl group. [ka]

[0039] When ring B is selected from a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group, and when ring A is a 6-membered fused 5-membered bicyclic heteroaryl group, ring A is [ka] Instead, L1 is selected from a bond, —C(O)—, or —C(O)NH—; R a is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2)n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NRA2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or any two adjacent or non-adjacent R a are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R b is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R B1 , -(CH2) n OR B1 , -(CH2) n C(O)R B1 , -(CH2) n C(O)OR B1 , -(CH2) n S(O) m R B1 , -(CH2) n NR B2 R B3 , -(CH2) n NR B2 C(O)OR B3 , -(CH2) n NR B2 C(O)(CH2) n1 R B3 , -(CH2) n NR B2 C(O)NR B2 R B3 , -(CH2) n C(O)NR B2 (CH2) n1 R B3 , -OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2)n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or any two adjacent or non-adjacent R b are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; Preferably, Or, any two R a and R bare linked to form a heterocyclyl or heteroaryl group, and the heterocyclyl and heteroaryl groups optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R C1 , -(CH2) n OR C1 , -(CH2) n C(O)R C1 , -(CH2) n C(O)OR C1 , -(CH2) n S(O) m R C1 , -(CH2) n NR C2 R C3 , -(CH2) n NR C2 C(O)OR C3 , -(CH2) n NR C2 C(O)(CH2) n1 R C3 , -(CH2) n NRC2 C(O)NR C2 R C3 , -(CH2) n C(O)NR C2 (CH2) n1 R C3 , -OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R C1 ~R C3are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or any two adjacent or non-adjacent R c are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R d is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R D1 , -(CH2) n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 R D3 , -(CH2) n NRD2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R D1 ~R D3are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or any two adjacent or non-adjacent R d are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; Or, any two R c and R d are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; n4 is 0, 1, 2, 3 or 4, and The compound is [ka] isn't it.

[0010] In a preferred embodiment of the present invention, the compound further comprises a compound represented by the general formula (III) or (III-1) [ka] As shown in where: M1 is selected from N or CH; M2 is selected from N or CH; M3 is selected from N or CH, and M4 is selected from N or CH.

[0011] In a more preferred embodiment of the present invention, ring A according to the present invention is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, ring A is C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; More preferably, ring A is selected from a 5- to 12-membered monocyclic heteroaryl group and an 8- to 12-membered bicyclic heteroaryl group; More preferably, ring A is a 5-membered monoheteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group or a 6-membered fused 6-membered bicyclic heteroaryl group; Even more preferably, ring A is a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazole group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, a pyridazinyl group, [ka] is selected from Even more preferably, ring A is a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazole group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, a pyridazinyl group, [ka] is selected from Preferably, it is a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, or a pyridazinyl group; Alternatively, ring A is selected from an 8- to 12-membered bicyclic heteroaryl group, an 8- to 12-membered heteroaryl-fused aryl group, an 8- to 14-membered heteroaryl-fused cycloalkyl group, or an 8- to 14-membered heteroaryl-fused heterocyclyl group, preferably [ka] is selected from More preferably, [ka] is selected from More preferably, [ka] is selected from.

[0012] In a preferred embodiment of the invention, the compound further has the general formula (IE) [ka] As shown in the figure.

[0013] In a preferred embodiment of the present invention, the compound is further represented by general formula (I-1′): [ka] where: Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; M5 is selected from N or CR5; R5 is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R arepresents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R A1 ~R A3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R a are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R b represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R B1 , -(CH2) n OR B1 , -(CH2) n C(O)R B1 , -(CH2) n C(O)OR B1 , -(CH2) n S(O) m R B1 , -(CH2) n NR B2 R B3 , -(CH2) n NR B2 C(O)OR B3 , -(CH2) n NR B2 C(O)(CH2) n1 R B3 , -(CH2) n NR B2 C(O)NR B2 R B3 , -(CH2) n C(O)NR B2 (CH2) n1 R B3 , -OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R B1 ~R B3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R b are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or, any two R a and R b are bonded to form a 5- to 12-membered heterocyclyl group or a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heterocyclyl group or the 5- to 12-membered heteroaryl group optionally contains deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or, R5 and R b are bonded to form a 5- to 12-membered heterocyclyl group or a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heterocyclyl group or the 5- to 12-membered heteroaryl group optionally contains deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R C1 , -(CH2) n OR C1 , -(CH2) n C(O)R C1 , -(CH2) n C(O)OR C1 , -(CH2) n S(O) m R C1 , -(CH2) n NR C2 R C3 , -(CH2) n NR C2 C(O)OR C3 , -(CH2) n NR C2 C(O)(CH2) n1 R C3 , -(CH2) n NR C2 C(O)NR C2 R C3 , -(CH2) n C(O)NR C2 (CH2) n1 R C3 , -OC(R C1 R C2 ) n (CH2) n1 RC3 or -(CH2) n NR C2 S(O) m R C3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R C1 ~R C3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R c are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R d represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R D1 , -(CH2) n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 RD3 , -(CH2) n NR D2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R D1 ~R D3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R d are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or, any two R c and R d are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4.

[0014] In a preferred embodiment of the present invention, the compound further comprises a compound represented by the general formula (I-1), (I-2), (I-3), (I-4) or (I-5): [ka] As shown in the figure.

[0015] In a more preferred embodiment of the present invention, ring B according to the present invention is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, ring B is C 3-6 selected from a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, ring B is C 3-6 selected from a cycloalkyl group, a phenyl group, a 5-membered nitrogen-containing heterocyclyl group, a 6-membered nitrogen-containing heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered nitrogen-containing heteroaryl group, a 6-membered nitrogen-containing heteroaryl group, a 5-membered fused 5-membered bicyclic nitrogen-containing heteroaryl group, a 5-membered fused 6-membered bicyclic nitrogen-containing heteroaryl group, a 6-membered fused 5-membered bicyclic nitrogen-containing heteroaryl group, or a 6-membered fused 6-membered bicyclic nitrogen-containing heteroaryl group; More preferably, Ring B is selected from pyridine, pyrimidine, pyridone or pyrimidone; Even more preferably, ring B is pyridine, pyrimidine, benzene, [ka] is selected from Even more preferably, ring B is pyridine, pyrimidine, benzene, [ka] is selected from More preferably, ring B is pyridine, pyrimidine, benzene, [ka] is selected from More preferably, ring B is pyridine, pyrimidine, benzene, [ka] is selected from More preferably, ring B is pyridine, pyrimidine, benzene, [ka] is selected from Preferably, ring B further comprises: [ka] may be selected from:

[0016] In a preferred embodiment of the present invention, the compound is further as shown in general formula (V). [ka]

[0017] In a preferred embodiment of the present invention, the compound is further as shown in general formula (III-A), (III-B), (III-C), (III-D), (III-E) or (III-F). [ka]

[0018] In a preferred embodiment of the present invention, the compound is further represented by general formula (II'): [ka] where: Ring C is C 3-12 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 an aryl group, a 5- to 14-membered heteroaryl group; Preferably, ring C is C 3-6a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered monoheteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, C 3-6 a cycloalkyl group, a phenyl group, a 5-membered nitrogen-containing heterocyclyl group, a 6-membered nitrogen-containing heterocyclyl group, a 7- to 10-membered bicyclic nitrogen-containing heterocyclyl group, a 5-membered nitrogen-containing heteroaryl group, a 5-membered fused 5-membered bicyclic nitrogen-containing heteroaryl group, a 5-membered fused 6-membered bicyclic nitrogen-containing heteroaryl group, a 6-membered fused 5-membered bicyclic nitrogen-containing heteroaryl group, or a 6-membered fused 6-membered bicyclic nitrogen-containing heteroaryl group; More preferably, ring C is a phenyl group, a pyrrolidinyl group, [ka] is selected from Even more preferably, ring C is pyridine, pyrimidine, benzene, [ka] is selected from Even more preferably, ring C is pyridine, pyrimidine, benzene, [ka] is selected from Preferably, ring C further comprises: [ka] may be selected from R b represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R B1 , -(CH2) n OR B1 , -(CH2) n C(O)R B1 , -(CH2) n C(O)OR B1 , -(CH2) n S(O) m R B1 , -(CH2) n NR B2 R B3 , -(CH2) n NR B2 C(O)OR B3 , -(CH2) n NR B2 C(O)(CH2) n1 R B3 , -(CH2) n NR B2 C(O)NR B2 R B3 , -(CH2) n C(O)NR B2 (CH2) n1 R B3 , -OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R B1 ~R B3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R b are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R C1 , -(CH2) n OR C1 , -(CH2) n C(O)R C1 , -(CH2) n C(O)OR C1 , -(CH2) n S(O) m R C1 , -(CH2) n NR C2 R C3 , -(CH2) n NR C2 C(O)OR C3 , -(CH2) n NR C2 C(O)(CH2) n1 R C3 , -(CH2) n NR C2 C(O)NR C2 R C3 , -(CH2) n C(O)NR C2 (CH2) n1 R C3 , -OC(R C1 R C2 ) n (CH2) n1 RC3 or -(CH2) n NR C2 S(O) m R C3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R C1 ~R C3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R c are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R d represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2) n R D1 , -(CH2) n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 RD3 , -(CH2) n NR D2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R D1 ~R D3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R d represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12 Aryl group, 5- to 14-membered heteroaryl group, -(CH2)n R D1 , -(CH2) n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 R D3 , -(CH2) n NR D2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-12The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R D1 ~R D3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R d are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or, any two R c and R dare linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 It may be further substituted with one or more substituents selected from aryl groups and 5- to 14-membered heteroaryl groups.

[0019] y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4.

[0020] In a further preferred embodiment of the present invention, the compound is further as shown in general formula (II'-1). [ka]

[0021] In a further preferred embodiment of the present invention, R a represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 R A3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R A1 ~R A3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; Preferably, R a represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R A1 , -(CH2) n OR A1 , -(CH2) n C(O)R A1 , -(CH2) n C(O)OR A1 , -(CH2) n S(O) m R A1 , -(CH2) n NR A2 R A3 , -(CH2) n NR A2 C(O)OR A3 , -(CH2) n NR A2 C(O)(CH2) n1 R A3 , -(CH2) n NR A2 C(O)NR A2 RA3 , -(CH2) n C(O)NR A2 (CH2) n1 R A3 , -OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; R A1 ~R A3are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from aryl groups and 5- to 12-membered heteroaryl groups.

[0022] In a further preferred embodiment of the present invention, R b represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R B1 , -(CH2) n OR B1 , -(CH2) n C(O)R B1 , -(CH2) n C(O)OR B1 , -(CH2) n S(O) m R B1 , -(CH2) n NR B2 R B3 , -(CH2) n NR B2 C(O)OR B3 , -(CH2) n NR B2 C(O)(CH2) n1 R B3 , -(CH2) n NR B2 C(O)NR B2 R B3 , -(CH2) n C(O)NR B2 (CH2) n1 R B3 , -OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2)n NR B2 S(O) m R B3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; R B1 ~R B3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from aryl groups and 5- to 12-membered heteroaryl groups.

[0023] In a further preferred embodiment of the present invention, R c represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R C1 , -(CH2) n OR C1 , -(CH2) n C(O)R C1 , -(CH2) n C(O)OR C1 , -(CH2) n S(O) m R C1 , -(CH2) n NR C2 R C3 , -(CH2) n NR C2 C(O)OR C3 , -(CH2) n NR C2 C(O)(CH2) n1 R C3 , -(CH2) n NR C2 C(O)NR C2 R C3 , -(CH2) n C(O)NR C2 (CH2) n1 R C3 , -OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; R C1 ~R C3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from aryl groups and 5- to 12-membered heteroaryl groups.

[0024] In a further preferred embodiment of the present invention, R d represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R D1 , -(CH2)n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 R D3 , -(CH2) n NR D2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R D1 ~R D3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; Preferably, R d represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R D1 , -(CH2) n OR D1 , -(CH2) n C(O)R D1 , -(CH2) n C(O)OR D1 , -(CH2) n S(O) m R D1 , -(CH2) n NR D2 R D3 , -(CH2) n NR D2 C(O)OR D3 , -(CH2) n NR D2 C(O)(CH2) n1 R D3 , -(CH2) n NR D2 C(O)NR D2 R D3 , -(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 )n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; R D1 ~R D3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from aryl groups and 5- to 12-membered heteroaryl groups.

[0025] In a further preferred embodiment of the present invention, R 4’ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R e1 , -(CH2) n OR e1 , -(CH2) n C(O)R e1 , -(CH2) n C(O)OR e1 , -(CH2) n S(O) m R e1 , -(CH2) n NR e2 R e3 , -(CH2) n NR e2 C(O)OR e3 , -(CH2) n NR e2 C(O)(CH2) n1 R e3 , -(CH2) n NR e2 C(O)NR e2 R e3 , -(CH2) n C(O)NR e2 (CH2) n1 R e3 , -OC(R e1 R e2 ) n (CH2) n1 R e3 or -(CH2) n NR e2 S(O) m R e3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R e1 ~R e3 are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; Preferably, R 4’ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R e1 , -(CH2) n OR e1 , -(CH2) n C(O)R e1 , -(CH2) n C(O)OR e1 , -(CH2) n S(O) m R e1 , -(CH2) n NR e2 R e3 , -(CH2) n NR e2 C(O)OR e3 , -(CH2) n NR e2 C(O)(CH2) n1 R e3 , -(CH2) n NRe2 C(O)NR e2 R e3 , -(CH2) n C(O)NR e2 (CH2) n1 R e3 , -OC(R e1 R e2 ) n (CH2) n1 R e3 or -(CH2) n NR e2 S(O) m R e3 wherein the amino group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, haloC 1-3 Alkoxy group, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may be optionally further substituted, and may optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group; R e1 ~R e3are each independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 12-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 12-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from aryl groups and 5- to 12-membered heteroaryl groups.

[0026] The present invention further provides a compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: X is an amino group, a methylthio group, a halogen, a boronic acid, or a boronic acid ester; The other groups are as described above.

[0027] The present invention further provides a method for preparing a compound represented by general formula (III-1), comprising the steps of: [ka] where: X1 is an amino group, a halogen, a boronic acid or a boronic ester; Reacting the compound of general formula (VI) with the compound of general formula (VI-1) to obtain the compound of general formula (III-1), The other groups are as described above.

[0028] The present invention further provides a compound represented by general formula (VI-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] where: R 11 is selected from hydrogen, an amino protecting group, a 5- to 6-membered heteroaryl group, and a 5- to 6-membered heterocyclyl group, wherein the 5- to 6-membered heteroaryl group and the 5- to 6-membered heterocyclyl group are optionally protected by deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C 6-14 further substituted with one or more substituents selected from the group consisting of aryl groups and 5- to 14-membered heteroaryl groups; the amino protecting group is selected from an allyloxycarbonyl group, a trifluoroacetyl group, a tert-butylsulfinyl 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenylmethoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl group, a p-toluenesulfonyl group, a p-methoxybenzyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a phthaloyl group, a tert-butoxycarbonyl group, a benzyl group, or a p-methoxyphenyl group; The general formula (VI-2) is more preferably as shown in the general formula (VI-3): [ka] where: X2 is an amino group, a halogen, a boronic acid, or a boronic ester, and each of the other groups is as described above.

[0029] The present invention further provides a method for preparing a compound represented by general formula (V), comprising the steps of: Method 1: [ka] where: X3 is a halogen, a boronic acid, or a boronic ester; Reacting the compound of general formula (VI-2) with the compound of general formula (VI-4) to obtain the compound of general formula (V), The other groups are as described above.

[0030] Method 2: [ka] where: X4 is a formaldehyde group, a hydroxymethyl group, or a halomethyl group; R 12 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 haloalkyl groups, Reacting the compound of general formula (VI-3) with the compound of general formula (VI-5) to obtain the compound of general formula (V), The other groups are as described above.

[0031] The present invention further relates to pharmaceutical compositions, which comprise a therapeutically effective amount of any of the compounds of general formula (I) as indicated and their stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0032] In some embodiments of the present invention, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt in the pharmaceutical composition based on the free base is 0.1% to 95%, preferably 5 to 70%, for example, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0033] In some embodiments of the present invention, the pharmaceutical composition is selected from a tablet, a capsule, a liquid formulation, or an injectable solution, preferably further comprising a filler, and optionally further comprising a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0034] In some embodiments of the invention, the pharmaceutical composition is an immediate release formulation or a sustained release formulation.

[0035] In some embodiments of the present invention, the pharmaceutical composition has a unit dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt, based on the free base, of 1 to 1000 mg, preferably 1 to 500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0036] In some embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof may be administered in any convenient manner, such as, for example, oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and a correspondingly prepared pharmaceutical composition.

[0037] In some embodiments of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt may be formulated as a liquid or solid preparation, for example, a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0038] The present invention further relates to the application of any one of the compounds of general formula (I) and their stereoisomers or pharmaceutically acceptable salts thereof, or said pharmaceutical compositions in the manufacture of PCSK9 inhibitor drugs.

[0039] The present invention further relates to the application of any one of the compounds of general formula (I) and their stereoisomers or pharmaceutically acceptable salts thereof, or said pharmaceutical composition, in the manufacture of an LDL-lowering drug.

[0040] The present invention further relates to the application of the compound of general formula (I) and its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or their related diseases or symptoms, preferably in the manufacture of a medicament for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipoprotein metabolism disorder, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0041] The present invention further relates to the application of the compound of general formula (I) and its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or their related diseases or symptoms, preferably in the manufacture of a medicament for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipoprotein metabolism disorder, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0042] The present invention further relates to a method for preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipoprotein dysbolism, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, which comprises administering to a patient a therapeutically effective amount of a compound according to the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0043] The present invention further provides methods of treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, conditions associated with PCSK9.

[0044] The present invention further relates to a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipidemia, lipoprotein metabolism disorders, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. DETAILED DESCRIPTION OF THE INVENTION

[0045] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0046] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include 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, and 5-methylhexyl groups. , 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, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available linkage site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups, and in the present invention, is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a haloalkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, or an alkyl group substituted with a hydroxy group.

[0047] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted, e.g., a "methylene group" refers to -CH-, an "ethylene group" refers to -(CH)-, a "propylene group" refers to -(CH)-, a "butylene group" refers to -(CH)-, etc. The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0048] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0049] The term "fused cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, fused cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes:

[0050] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples of which include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups.

[0051] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or S(O). m(wherein m is an integer of 0 to 2), but does not include the ring moieties -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably it contains 3 to 8 ring atoms, most preferably it contains 3 to 8 ring atoms, and even more preferably it is a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and includes a nitrogen-containing monocyclic heterocyclyl group, a nitrogen-containing spiroheterocyclyl group, or a nitrogen-containing fused heterocyclyl group, or preferably it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, and even more preferably it is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl group containing 1 to 3 nitrogen and / or oxygen atoms.

[0052] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, and pyranyl groups, and preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazacycloheptyl, and piperazinyl groups. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups, where such spirocyclic, fused-ring, and bridged-ring heterocyclyl groups are optionally linked to other groups via a single bond or further tandemly linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0053] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more ring atoms is nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings constituting it, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered fused 5-membered or 5-membered fused 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes:

[0054] The ring of the heterocyclyl group may be fused onto the ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the base skeleton is a heterocyclyl group, non-limiting examples of which include: [ka] Includes:

[0055] Heterocyclyl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0056] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl groups. Phenyle is more preferred. The ring of the aryl group may be fused to a heteroaryl group, heterocyclyl group, or cycloalkyl group, including 5- to 10-membered benzoheteroaryl groups, 3- to 8-membered benzocycloalkyl groups, and 3- to 8-membered benzoheteroalkyl groups, preferably 5- to 6-membered benzoheteroaryl groups, 3- to 6-membered benzocycloalkyl groups, and 3- to 6-membered benzoheteroalkyl groups, where the heterocyclyl group is a heterocyclyl group containing 1 to 3 nitrogen, oxygen, or sulfur atoms, or further containing a 3-membered nitrogen-containing fused ring containing a benzene ring.

[0057] Here, the ring connected to the basic skeleton is an aryl group ring, and non-limiting examples thereof include: [ka] Includes:

[0058] The aryl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, oxo groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0059] The term "heteroaryl group" refers to a heteroaromatic ring system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably a 5- or 6-membered monocyclic heteroaryl group or an 8 to 12-membered bicyclic heteroaryl group, such as an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, an oxadiazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, a pyrazolyl group, a triazinyl group, or a pyridazinyl group, preferably a triazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a pyrimidinyl group, or a thiazolyl group, more preferably a pyrazolyl group, a pyrrolyl group, or an oxazolyl group.

[0060] The bicyclic heteroaryl group is preferably a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, a 6-membered fused 6-membered bicyclic heteroaryl group, and non-limiting examples thereof are: [ka] Includes.

[0061] The ring of the heteroaryl group may be fused onto the ring of an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring connected to the basic skeleton is the ring of the heteroaryl group, non-limiting examples of which include: [ka] Includes:

[0062] Heteroaryl groups may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, oxo groups, and carboxylate groups.

[0063] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0064] "Haloalkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0065] A "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0066] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl group is as defined above.

[0067] An "alkenyl group" is a chain-like alkenyl group, further referred to as an alkylene group, wherein the alkenyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0068] An "alkynyl group" is (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0069] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of alkenyl group is as defined above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl groups. An alkenylcarbonyl group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0070] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be any one or more of A, B, and C.

[0071] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0072] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0073] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and a person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0074] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof 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 and promote absorption of the active ingredients, thereby exerting their biological activity.

[0075] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity. [Example]

[0076] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0077] Example The structures of compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (DO). The internal standard (when available) was tetramethylsilane (TMS).

[0078] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C). 18 A 150 x 4.6 mm chromatography column was used.

[0079] Thin-layer chromatography silica gel plates used were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with 0.15mm to 0.20mm specifications for TLC and 0.4mm to 0.5mm specifications for product separation and purification by thin-layer chromatography. Column chromatography generally used Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0080] The starting materials in the examples of the present invention are either known and commercially available, or can be synthesized using or according to methods known in the art.

[0081] Unless otherwise specified, all reactions of the present invention were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents were dry solvents, and the reaction temperatures were in degrees Celsius.

[0082] The eluent system for silica gel column chromatography and the developer system for thin layer chromatography used to purify the intermediates and compounds in the examples included A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and could also be adjusted by adding small amounts of alkaline or acidic reagents such as triethylamine and acetic acid.

[0083] Unless otherwise specified, in the examples of the present invention, the ratio of the mobile phases under the HPLC chiral resolution conditions and the HPLC chiral analysis conditions was a volume ratio.

[0084] Intermediate 1 (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine Intermediate 1 was obtained by synthesis in accordance with the manufacturing method described in International Publication No. 2020 / 150473. MS m / z(ESI):245.1[M+H] + .

[0085] Intermediate 1 can also be obtained in the following manner. [ka]

[0086] Step 1 2-Chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), (1S,3S)-tert-butyl 3-aminocyclopentylcarbamate (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the reaction was heated to 100° C. and stirred for 5 h. The reaction was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give tert-butyl (1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylcarboxylate 1B (2.1 g) in a yield of 55.1%. MS m / z(ESI):345.2[M+H] + .

[0087] Step 2 1B (2.1 g, 6.1 mmol) was dissolved in methanol (10 mL), a solution of hydrochloric acid in dioxane (4 M, 20 mL) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated, and a solution of ammonia in methanol (7 M, 10 mL) was added to adjust the pH to slightly alkaline. After reconcentration, the residue was purified by silica gel chromatography (elution system A) and separated to give (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g) was obtained, with a yield of 87.3%. MS m / z(ESI):245.1[M+H] + .

[0088] Intermediate 2 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0089] Step 1 2-Fluoro-5-iodopyridine 2A (5 g, 22.4 mmol), 2-hydroxypyridine (2.35 g, 24.7 mmol), cuprous iodide (427 mg, 2.24 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (159 mg, 1.12 mmol), and cesium carbonate (9.5 g, 29.2 mmol) were dissolved in 1,4-dioxane (75 mL), and the reaction was heated to 100 °C and stirred for 16 h. The reaction was cooled to room temperature, poured into 100 mL of water, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 6'-fluoro-2H-[1,3'-bipyridin]-2-one 2B (3.1 g), yield 72.7%. MS m / z (ESI): 191.1 [M + H] + .

[0090] Step 2 (1S,3S)-tert-Butyl 3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridin]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were dissolved in dimethyl sulfoxide (30 mL), and the reaction was heated to 130 °C and stirred for 16 h. The reaction was cooled to room temperature, poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g), yield 78.4%. MS m / z (ESI): 371.2 [M + H] + .

[0091] Step 3 tert-Butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g, 7.83 mmol) was dissolved in 4 M hydrochloric acid in dioxane (30 mL), and the reaction was stirred at room temperature for 3 h. The reaction was concentrated, and the residue was purified by reverse-phase chromatography (eluent system C) to give 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one intermediate 2 (1.5 g), 70.9% yield. MS m / z (ESI): 271.2 [M + H] + .

[0092] Example 1 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 1 can also be obtained in the following manner. [ka]

[0093] Step 1 Under nitrogen gas protection, 1a (10.00 g, 51.55 mmol), bis(pinacolato)diboron (19.64 g, 77.33 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (3.79 g, 5.16 mmol), and potassium acetate (10.10 g, 103.11 mmol) were dissolved in 1,4-dioxane (200 mL) and cooled to 90°C. ℃ The reaction mixture was heated to rt and stirred for 3 h. The reaction mixture was filtered and the organic phase was concentrated to give crude (5,6-difluoro-3-pyridyl)boronic acid 1b (7.60 g), which was used directly in the next step without further purification. MS m / z(ESI):160.0[M+H] + .

[0094] Step 2 1b (6.00 g, 37.76 mmol) and hydrogen peroxide (12.84 g, 113.28 mmol, 30% aqueous solution) were dissolved in 1,4-dioxane (100 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give 5,6-difluoro-3-hydroxypyridine 1c (3.20 g) in a 64.6% yield. MS m / z (ESI): 132.0 [M + H] + .

[0095] Step 3 1c (5.00 g, 38.14 mmol) and cesium carbonate (18.60 g, 57.22 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature and stirred for 30 minutes. Under nitrogen gas protection, sodium 2-chloro-2,2-difluoroacetate (11.90 g, 76.29 mmol) was added to the reaction mixture, which was then heated to 90 °C and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with water (50 mL) and saturated sodium chloride (50 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give 5-(difluoromethoxy)-2,3-difluoropyridine 1d (2.60 g) in a 37.6% yield. MS m / z (ESI): 182.0 [M + H] + .

[0096] Step 4 Following the synthesis method of Step 1 of Intermediate 1, 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 1 was synthesized. MS m / z(ESI):432.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.92(d,1H),7.80(d,1H),7.60(m,1H),7.42(m,3H),7.04(t,1H),6.93(d,1H),6.72(m ,1H),6.53(d,1H),6.44(m,1H),6.27(m,1H),4.45(m,1H),4.33(m,1H),2.11(m,2H),1.93(m,2H),1.52(m,2H).

[0097] Example 4 6'-(((1S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0098] Step 1 3-Amino-1,2,4-triazin-6(1H)-one 4a (1 g, 8.92 mmol), trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (3.35 g, 13.4 mmol), and 1,4-diazabicyclo[2.2.2]octane (2.0 g, 17.8 mmol) were dissolved in anhydrous toluene (15 mL), and the reaction was heated to 80 °C and stirred for 2 h. The reaction was cooled to room temperature, washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 6-(difluoromethoxy)-1,2,4-triazin-3-amine 4b (430 mg) in 29.7% yield. MS m / z (ESI): 163.0 [M + H] + .

[0099] Step 2 Under nitrogen gas protection, 6-(difluoromethoxy)-1,2,4-triazin-3-amine 4b (430 mg, 2.65 mmol), tert-butyl nitrite (410 mg, 3.98 mmol), and cuprous chloride (341 mg, 3.45 mmol) were dissolved in anhydrous acetonitrile (6 mL), and the reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (260 mg) in a 54.0% yield. MS m / z (ESI): 182.0 [M + H] + .

[0100] Step 3 Under nitrogen gas protection, intermediate 2 (80 mg, 0.256 mmol), 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (54 mg, 0.256 mmol), and N,N-diisopropylethylamine (115 mg, 0.888 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The organic layer was washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by reverse phase chromatography (ammonium bicarbonate system) to give 6'-(((S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 4 (37 mg), 30.1% yield. MS m / z(ESI):416.2[M+H] + .

[0101] Example 12 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0102] Step 1 3-Chloro-1,2,4-triazole 12a (1 g, 9.66 mmol), cyclopropylboronic acid (1.66 g, 19.3 mmol), copper acetate (2.63 g, 14.5 mmol), 2,2'-bipyridine (2.26 g, 14.5 mmol), and sodium carbonate (2.05 g, 19.3 mmol) were dissolved in 1,2-dichloroethane (20 mL), and the reaction was heated to 80 °C and stirred for 3 h. The reaction was cooled to room temperature, filtered, and the filtrate was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to give 3-chloro-1-cyclopropyl-1H-1,2,4-triazole 12b (340 mg) in 24.5% yield. MS m / z (ESI): 144.0 [M + H] + .

[0103] Step 2 The target product, 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 12, was synthesized according to the synthesis method of Example 4. MS m / z (ESI): 378.2 [M + H] + . 1 H NMR(400MHz,CD3OD)δ8.02(s,1H),7.94(d,1H),7.64-7.56(m,2H),7.44(dd,1H),6.67-6.57(m,2H),6.46(t,1H),4.34-4.2 9(m,1H),4.13-4.05(m,1H),3.52-3.44(m,1H),2.28-2.17(m,2H),2.03-1.95(m,2H),1.65-1.52(m,2H),1.14-0.97(m,4H).

[0104] Example 15 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0105] Step 1 Under nitrogen gas protection, 3-bromo-5-chloro-1,2,4-thiadiazole 15a (400 mg, 2.01 mmol), difluoromethyl trifluoromethanesulfonate (803 mg, 4.02 mmol), tris(dibenzylideneindeneacetone)dipalladium (184 mg, 0.201 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (170 mg, 0.401 mmol), and potassium hydroxide (169 mg, 3.01 mmol) were dissolved in 1,4-dioxane (6 mL), and the reaction mixture was heated to 100°C and reacted for 6 h. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) was added. The organic phase was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to give 3-chloro-5-(difluoromethoxy)-1,2,4-thiadiazole 15b (130 mg) in a yield of 28.1%. MS m / z (ESI): 187.0 [M + H] + .

[0106] Step 2 The target product, 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 15, was synthesized according to the synthesis method of Example 4. MS m / z(ESI):421.1[M+H] + .

[0107] Example 20 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0108] Step 1 2-Chloropyrrolo[2,1-f][1,2,4]triazine 20a (50 mg, 0.326 mmol), intermediate 2 (88 mg, 0.326 mmol), and diisopropylethylamine (84 mg, 0.651 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the reaction was heated to 110 °C and stirred for 16 h. The reaction mixture was allowed to cool to room temperature, and saturated sodium chloride solution (10 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 20 (85 mg), yield: 67.4%. MS m / z(ESI):388.2[M+H] + . 1 H NMR(400MHz,CD3OD)δ8.67(s,1H),7.98(s,1H),7.63-7.57(m,2H),7.51(dd,1H),7.45(d,1H),6.71(m,2H) ,6.61(dt,2H),6.46(td,1H),4.39-4.26(m,2H),2.34-2.17(m,2H),2.13-1.98(m,2H),1.71-1.57(m,2H).

[0109] Example 22 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 22 can also be synthesized by the following method. [ka]

[0110] Step 1 tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1.0 g, 4.99 mmol) and 4-methoxybenzaldehyde (816 mg, 5.99 mmol) were dissolved in methanol (10 mL), and acetic acid (300 mg, 4.99 mmol) was added with stirring. The reaction was stirred at 17 °C for 16 h. Sodium cyanoborohydride (941 mg, 14.98 mmol) was added to the reaction, and the reaction was stirred for 1 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-((4-methoxybenzyl)amino)cyclopentyl)carbamate 22a (1.2 g), yield: 75%. MS m / z(ESI):321.3[M+H] + .

[0111] Step 2 22a (1.3 g, 4.06 mmol), cyanogen bromide (645 mg, 6.09 mmol), and N,N-diisopropylethylamine (1.0 g, 8.11 mmol) were dissolved in tetrahydrofuran (10 mL) and added with stirring. The reaction was stirred at 18 °C for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-(N-(4-methoxybenzyl)cyanamido)cyclopentyl)carbamate 22b (1.2 g), yield 85.6%. MS m / z(ESI):346.1[M+H] + .

[0112] Step 3 Under nitrogen gas protection, 22b (1.15 g, 3.33 mmol), hydroxylamine hydrochloride (578.4 mg, 8.32 mmol), and triethylamine (1.35 g, 13.32 mmol) were dissolved in isopropanol (10 mL), heated to 90° C., and stirred for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent C) to give tert-butyl ((1S,3S)-3-((E)-2-hydroxy-1-(4-methoxybenzyl)guanidino)cyclopentyl)carbamate 22c (1.0 g) in a 79.4% yield. MS m / z (ESI): 379.2 [M + H] + .

[0113] Step 4 2,2-Difluorocyclopropane-1-carboxylic acid (419 mg, 3.43 mmol) and carbonyldiimidazole (557 mg, 3.43 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature and stirred for 0.5 h. 22c (1.0 g, 2.64 mmol) was dissolved in N,N-dimethylformamide (2 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h, then heated to 100 °C and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride (60 mL × 3), dried, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)(4-methoxybenzyl)amino)cyclopentyl)carbamate 22d (390 mg), the yield was 31.8%. MS m / z(ESI):465.3[M+H] + .

[0114] Step 5 22d (390 mg, 0.84 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction was stirred at 18 °C for 1 h. The reaction was concentrated, and ammonia in methanol (7 M) was added to the residue, adjusting the pH to 8. The reaction was concentrated, and the residue was purified by reverse-phase chromatography (aqueous ammonia system) to give (1S,3S)-N1-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine 22e (70 mg), 34.1% yield. MS m / z(ESI):245.2[M+H] + .

[0115] Step 6 22e (60 mg, 0.24 mmol), 2B (60 mg, 0.32 mmol), and N,N-diisopropylethylamine (95 mg, 0.74 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 16 h. The reaction was filtered, and the filtrate was purified by preparative HPLC (ammonium carbonate system) to give 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 22 (13.5 mg) in 13.1% yield. MS m / z(ESI):415.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ7.97(s,1H),7.45(dd,1H),7.35-7.28(m,1H),7.22(dd,1H),6.58(d,1H),6.37(d,1H),6.1 6(t,1H),4.67(d,1H),4.32(d,1H),4.25-4.15(m,1H),4.05-3.95(m,1H),2.85-2.75(m,1H),2.33-1.86(m,8H).

[0116] Example 26 6'-(((1S,3S)-3-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 26 can also be synthesized by referring to the following production method. [ka]

[0117] Step 1 [1,2,4]Triazolo[1,5-a]pyridin-2-amine 26a (2.7 g, 20.13 mmol) and platinum dioxide (914 mg, 4.03 mmol) were dissolved in a mixture of hydrochloric acid (12 M, 3 mL) and methanol (3 mL) under a hydrogen gas atmosphere at 25 °C and stirred for 48 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was neutralized to pH = 10 with saturated sodium bicarbonate solution. The mixture was extracted five times with a dichloromethane / isopropanol (3:1) mixture. The organic phase was dried, filtered, and concentrated to give 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 26b (2.5 g) in 89.9% yield. MS m / z (ESI): 139.2 [M + H] + .

[0118] Step 2 Copper bromide (711.0 mg, 3.18 mmol) and tert-butyl nitrite (820.9 mg, 7.96 mmol) were dissolved in acetonitrile (6 mL), and 26b (220 mg, 1.59 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 0.5 h, then heated to 60 °C and stirred for 1 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL) and filtered. The organic phase was washed with water (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 26c (200 mg) in a 62.2% yield. MS m / z (ESI): 204.0 [M + H] + .

[0119] Step 3 Under nitrogen gas protection, 26c (597.9 mg, 2.96 mmol), Intermediate 2 (200 mg, 0.74 mmol), sodium tert-butanol (213.3 mg, 2.22 mmol), tris(dibenzylideneacetone)palladium (135.5 mg, 0.15 mmol), and Xantphos (171.2 mg, 0.3 mmol) were dissolved in 1,4-dioxane (8 mL) and heated to 130 °C in a microwave oven with stirring for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL), and the organic phase was washed with water and saturated brine, dried, filtered, and concentrated. The residue was purified by preparative HPLC (formic acid system) to give 6'-(((1S,3S)-3-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 26 (9.5 mg), yield: 2.9%. MS m / z (ESI): 392.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ7.91(d,1H),7.60(dd,1H),7.48(t,1H),7.38(dd,1H),6.87(d,1H),6.51(d,1H),6.44(d,1H) ,6.27(t,1H),5.69(d,1H),4.27(q,1H),3.95(q,1H),3.83(t,2H),2.62(t,2H),2.19-1.70(m,8H),1.53-1.39(m,2H).

[0120] Example 27 6'-((3-(((1S,3S)-7-fluoro-[1,2,4]triazazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0121] Step 1 7-Fluoro-[1,2,4]triazazolo[1,5-a]pyridin-2-amine 27a (100 mg, 0.657 mmol) was dissolved in acetonitrile and stirred in an ice bath. Sodium nitrite (91 mg, 1.31 mmol) was added to the reaction mixture and stirred for 1 minute. Hydrochloric acid (4 M, 0.41 mL) was added dropwise to the reaction mixture, and the reaction mixture was warmed to room temperature and stirred. Completion of the reaction was confirmed using a thin-layer chromatography plate. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture until the pH reached 7. The reaction mixture was extracted with dichloromethane (10 mL × 3). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (eluent system A) to give 2-chloro-7-fluoro-[1,2,4]triazazolo[1,5-a]pyridine 27b (65 mg) in 77.5% yield. MS m / z (ESI): 172.1 [M + H] + .

[0122] Step 2 The target product, 6'-((3-(((1S,3S)-7-fluoro-[1,2,4]triazazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 27, was synthesized according to the synthesis method of Step 1 of Example 20.

[0123] Step 2 can also be synthesized by referring to the method below.

[0124] Under nitrogen gas protection, 27b (80 mg, 0.37 mmol), 27c (100 mg, 0.37 mmol), cesium carbonate (241.3 mg, 0.74 mmol), Pd2dba3 (67.8 mg, 0.074 mmol), and xantphos (85.7 mg, 0.15 mmol) were dissolved in 1',4-dioxane (2 mL). The reaction mixture was heated to 130 °C and incubated in a microwave oven for 2 hours. The reaction mixture was heated to 130 °C under nitrogen gas protection for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (alkaline system) to give 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 27 (6.6 mg), yield: 4.08%. MS m / z(ESI):406.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.69-6.59(m,1H),7.92(d,1H),7.60(dd,1H),7.51-7.35(m,2H),7.27(dd,1H),6.97-6.82(m,2H),6.74(d,1H) ,6.52(d,1H),6.44(d,1H),6.26(t,1H),4.35-4.28(m,1H),4.20-4.10(m,1H),2.20-2.07(m,2H),2.00-1.82(m,2H),1.60-1.42(m,2H).

[0125] Example 38 6'-(((1S,3S)-3-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 38 can also be synthesized by the following method. [ka]

[0126] Step 1 Following the synthesis method of Example 20, methyl 2-chloropyrimidine-5-carboxylate 38a was used as the starting material to synthesize 2-(((1S,3S)-3-((2-one-2H-[1,3'-bipyridin]-6-yl)amino)cyclopentyl)amino)pyridine-5-carboxylate 38b. MS m / z(ESI):407.2[M+H] + .

[0127] Step 2 Under nitrogen gas protection, 38b (35 mg, 0.086 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 0 °C. A 1 M solution of methylmagnesium bromide in tetrahydrofuran (2 mL) was added dropwise to the reaction mixture, and the mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with methanol, concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to give the desired product (9 mg) in a 25.7% yield. MS m / z(ESI):407.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.33(s,2H),7.92 (d,1H),7.60(dd,1H),7.48(ddd,1H),7.39(dd,1H),7.09(d,1H),6.93(d,1H),6.53(d,1H),6.44(d,1H),6.27( td,1H),5.01(s,1H),4.37-4.27(m,2H),2.16-2.07(m,2H),1.93-1.81(m,2H),1.54-1.43(m,2H),1.39(s,6H).

[0128] Example 47 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one [ka]

[0129] Step 1 Under nitrogen gas protection, 3-bromo-4H-quinolizin-4-one 47a (1.0 g, 4.46 mmol), (6-fluoropyridin-3-yl)boronic acid (755 mg, 5.36 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (162 mg, 0.223 mmol), and potassium carbonate (1.54 g, 11.5 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL), and the reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give 3-(6-fluoropyridin-3-yl)-4H-quinolizin-4-one 47b (360 mg) in 34% yield. MS m / z(ESI):241.1[M+H] + .

[0130] Step 2 3-(6-Fluoropyridin-3-yl)-4H-quinolin-4-one 47b (100 mg, 0.416 mmol), Intermediate 1 (102 mg, 0.416 mmol), and N,N-diisopropylethylamine (207 μL, 1.25 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 24 h. The reaction mixture was purified by preparative HPLC (formic acid system) to give the desired product, 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (47 mg), in 24% yield. MS m / z(ESI):465.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.54(s,1H),8.24(s,2H),8.00(d,2H),7.7 8(d,1H),7.56-7.44(m,2H),7.25-7.17(m,1H),7.03(t,1H),6.95(d,1H),6.60(d 1H),4.32(h,2H),2.23-2.08(m,2H),1.90(dp,2H),1.54(ddt,2H).

[0131] Example 47 can also be obtained by synthesis using the following method. [ka]

[0132] Step 1 47c (120 mg, 0.405 mmol), (6-fluoropyridin-3-yl)boronic acid (103 mg, 0.729 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (29 mg, 0.041 mmol), and potassium carbonate (140 mg, 1.01 mmol) were dissolved in a mixture of dioxane (1.5 mL) and water (0.15 mL), and the reaction was heated to 90 °C and stirred for 16 h. The reaction was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give ethyl 3-(6-fluoropyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylate 47d (110 mg) in 87% yield. MS m / z(ESI):313.1[M+H] + .

[0133] Step 2 47d (102 mg, 0.328 mmol), Intermediate 1 (80 mg, 0.328 mmol), and N,N-diisopropylethylamine (143 μL, 0.819 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 24 h. The reaction was purified by preparative HPLC (formic acid system) to give ethyl 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminoamino)pyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylate 47e (53 mg) in 30% yield. MS m / z (ESI): 537.2 [M + H] + .

[0134] Step 3 47e (35 mg, 0.065 mmol) was dissolved in hydrochloric acid (12 M, 5 mL), and the reaction was heated to 100° C. and stirred for 1.5 h. The reaction was purified by preparative HPLC (formic acid system) to give the desired product, 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (21 mg), in 69% yield. MS m / z(ESI):465.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.54(s,1H),8.24(s,2H),8.00(d,2H),7.7 8(d,1H),7.56-7.44(m,2H),7.25-7.17(m,1H),7.03(t,1H),6.95(d,1H),6.60(d 1H),4.32(h,2H),2.23-2.08(m,2H),1.90(dp,2H),1.54(ddt,2H).

[0135] Example 52 (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine Example 52 can also be synthesized by the following method. [ka]

[0136] Step 1 Under nitrogen gas protection, 7-bromopyrazolo[1,5-a]pyridine 52a (150 mg, 0.76 mmol), (6-fluoropyridin-3-yl)boronic acid (139 mg, 0.99 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (56 mg, 0.08 mmol), and cesium carbonate (496 mg, 1.52 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL). The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine 52b (155 mg) in 95.49% yield. MS m / z(ESI):214.1[M+H] + .

[0137] Step 2 Intermediate 1 (60 mg, 0.25 mmol), 52b (105 mg, 0.49 mmol), and N,N-dimethylethylamine (79 mg, 0.61 mmol) were dissolved in dimethyl sulfoxide (1 mL), and the reaction mixture was heated to 130 °C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was separated by reverse-phase HPLC (ammonium bicarbonate system) to obtain (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 52 (42.3 mg) was obtained, with a yield of 39.36%. MS m / z(ESI):438.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.56(d,1H),8.24(s,2H),8.07-7.97(m,2H),7.63(d,1H),7.51(d,1H),7.29-7.23(m,1H),7.07(d,1H),7.2 2-6.85(m,1H),6.95(d,1H),6.68(d,1H),6.59(d,1H),4.47-4.23(m,2H),2.24-2.05(m,2H),1.99-1.84(m,2H),1.63-1.45(m,2H).

[0138] Example 53 (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazole[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine [ka]

[0139] Step 1 Under nitrogen gas protection, 8-bromoimidazole[1,2-a]pyridine 53a (1.0 g, 5.08 mmol), (6-fluoropyridin-3-yl)boronic acid (858 mg, 6.09 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (184 mg, 0.254 mmol), and potassium carbonate (1.75 g, 12.7 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL), and the reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give 8-(6-fluoropyridin-3-yl)imidazole[1,2-a]pyridine 53b (415 mg) in 38% yield. MS m / z(ESI):214.1[M+H] + .

[0140] Step 2 The target product (1S,3S)-N 1-(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazol[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine 53 was obtained. MS m / z(ESI):438.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.81(d,1H),8.46(d,1H),8.25-8.18(m,3H),7.99(d,1H),7.59(d,1H),7.51(d,1H),7.36(d,1H),7. 03(t,1H),6.93(t,1H),6.88-6.81(m,1H),6.56(d,1H),4.33(dq,2H),2.22-2.07(m,2H),2.00-1.85(m,2H),1.53(ddd,2H).

[0141] Example 56 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazol[4,5-b]pyrazin-2-one [ka]

[0142] Step 1 Under nitrogen gas protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.78 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol), and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (120 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL × 3), the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography to give 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazin-2-one 56b (1.4 g, pale yellow solid), the yield was 57.87%. MS m / z(ESI):246.1[M+H] + .

[0143] Step 2 Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazin-2-one 56b (77 mg, 0.32 mmol) and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL) and the reaction was heated to 130 °C and stirred for 48 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase HPLC (ammonium bicarbonate system) to give 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazin-2-one 56 (41 mg, white solid) in 30.47% yield. MS m / z(ESI):470.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(m,2H),7.26-6.82(m,1H), 6.97(d,1H),6.59(d,1H),4.42-4.19(m,2H),3.40(s,3H),2.22-2.05(m,2H),1.95-1.82(m,2H),1.61-1.42(m,2H).

[0144] Example 57 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one [ka]

[0145] Step 1 Under nitrogen gas protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.59 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol), and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, saturated sodium chloride solution (120 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL × 3), the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 57b (1.3 g), the yield was 57.49%. MS m / z(ESI):230.1[M+H] + .

[0146] Step 2 Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 57b (72 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the reaction was heated to 130 °C and stirred for 48 h. The reaction was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase HPLC (formic acid system) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 57 (46 mg) in 35.4% yield. MS m / z(ESI):454.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.35(d,1H),8.24(s,2H),8.11(d,1H),7.88(d,1H),7.66-7.57(m,1H),7.48(d,1H),7.25- 6.82(m,1H),6.71(s,1H),6.57(d,1H),4.93(s,2H),4.37-4.19(m,2H),2.22-2.04(m,2H),1.96-1.80(m,2H),1.60-1.41(m,2H).

[0147] Example 63 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 63 can also be synthesized by the following method. [ka]

[0148] Step 1 63a (3.5 g, 20 mmol) was dissolved in acetonitrile (50 mL), tert-butyl nitrite (3.09 g, 30 mmol) was added, and the mixture was stirred at room temperature for 30 min. Copper bromide (6.7 g, 30 mmol) was added, and the mixture was stirred at room temperature for 1 h. After that, the reaction mixture was heated to 50° C. and stirred for 1 h. The reaction mixture was filtered and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give 3,6-dibromo-1,2,4-triazine 63b (1.3 g), 27.3% yield. MS m / z(ESI):237.9[M+H] + .

[0149] Step 2 63b (1.3 g, 5.44 mmol), (1S,3S)-tert-butyl 3-aminocyclopentylcarbamate (1.2 g, 5.99 mmol), and diisopropylethylamine (1.41 g, 10.88 mmol) were dissolved in dioxane (20 mL), and the reaction mixture was heated to 80 °C and stirred for 2 h. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was washed with water (30 mL × 3) and saturated sodium chloride, dried, concentrated, and the residue was purified by silica gel column chromatography (eluent system B) to give tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentane)carbamate 63c (1.5 g), 76.9% yield. MS m / z(ESI):358.1[M+H] + .

[0150] Step 3 63c (1.5 g, 4.19 mmol), cyclopropylboronic acid (719 mg, 8.38 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (306.4 mg, 0.42 mmol), and sodium carbonate (1.33 g, 12.56 mmol) were dissolved in dioxane (20 mL) and water (5 mL). The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was filtered, ethyl acetate (100 mL) was added, and the organic phase was washed with water (30 mL × 3) and saturated sodium chloride, dried, concentrated, and the residue was purified by silica gel column chromatography (eluent system B) to give tert-butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentane)carbamate 63d (400 mg) in 29.9% yield. MS m / z(ESI):320.2[M+H] + .

[0151] Step 4 63d (400 mg, 1.25 mmol) was dissolved in methanol (5 mL), 4 M hydrochloric acid in dioxane (5 mL) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated, and ammonia in methanol was added to adjust the pH to slightly alkaline. After reconcentration, the residue was separated by silica gel column chromatography (eluent system A) to give ((1S,3S)-N 1 -((6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 63e (120 mg) was obtained, with a yield of 43.6%. MS m / z(ESI):220.2[M+H] + .

[0152] Step 5 63e (100 mg, 0.456 mmol), 2B (141.3 mg, 0.684 mmol), tris(dibenzylideneacetone)dipalladium (41.76 mg, 0.0456 mmol), 2-biscyclohexylphosphine-2',6'-diisopropoxybiphenyl (42.56 mg, 0.091 mmol), and sodium tert-butanol (131.5 mg, 1.37 mmol) were dissolved in dioxane (10 mL), and the reaction was heated to 100 °C and stirred for 15 h. Ethyl acetate (30 mL) was added to the reaction mixture, and the organic phase was washed with water (10 mL × 3) and saturated sodium chloride, dried, and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give the desired product 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one 63 (26 mg) in a yield of 14.6%. MS m / z(ESI):390.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.92(d,1H),7.60(dd,1H),7.54(s,1H),7.47(td,1H),7.38(dd,1H),6.93(d,1H),6.53(d,1H),6 .44(d,1H),6.27(t,1H),4.34(m,2H),2.18-2.10(m,2H),2.08-2.02(m,1H),1.98-1.85(m,2H),1.60-1.39(m,2H),1.00-0.86(m,4H).

[0153] Example 64 6''-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropan-2-yl)-2H-[1,3''-bipyridin]-2-one Example 64 can also be synthesized by the following method. [ka]

[0154] Step 1 The target product, 6″-fluoro-3-(2-hydroxypropan-2-yl)-2H-[1,3″-bipyridin]-2-one 64b, was synthesized according to the synthesis method of Step 1 of Intermediate 2. MS m / z (ESI): 249.1 [M + H] + .

[0155] Step 2 64b (150 mg, 0.604 mmol), Intermediate 1 (98 mg, 0.403 mmol), and N,N-diisopropylethylamine (104 mg, 0.806 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 24 h. The reaction mixture was purified by preparative HPLC (formic acid system) to give 6"-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropan-2-yl)-2H-[1,3"-bipyridin]-2-one 64 (62 mg) in 32.6% yield. MS m / z(ESI):473.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ8.18(s,2H),8.03(d,1H),7.55(dd,1H),7.41(dd,1H),7.29(dd,1H),6.47(d,1H),6.41(t,1H)6.31(t ,1H),5.89(s,1H),5.22(d,1H),5.00(s,1H),4.41(d,1H),4.26(d,1H),2.33(m,2H),2.05(m,2H),1.77(s,2H),1.58(s,6H).

[0156] Example 68 6''-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one Example 68 can also be synthesized by the following method. [ka]

[0157] Step 1 2-Chloropyrrolo[2,1-f][1,2,4]triazine 68a (50 mg, 0.325 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanedi(tetrafluoroborate) (173 mg, 0.488 mmol) were dissolved in acetonitrile (3 mL), and the reaction was heated to 80 °C in a microwave oven and stirred for 1 h. The reaction was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give 2-chloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine 68b (25 mg) in 44.7% yield. MS m / z (ESI): 172.0 [M + H] + .

[0158] Step 2 68b (25 mg, 0.146 mmol), Intermediate 2 (39.4 mg, 0.146 mmol), and cesium carbonate (95.0 g, 0.291 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction was heated to 100 °C and stirred for 2 h. The reaction was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6"-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3"-bipyridin]-2-one 68 (27 mg) in 45.7% yield. MS m / z(ESI):406.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.61(dd,1H),7.48(td,1H),7.40(dd,1H),7.16(d,1H),6.96(d,1H),6.67(t,1H) ),6.53(d,1H),6.44(d,1H),6.37(t,1H),6.27(t,1H),4.34-4.19(m,2H),2.21-2.11(m,2H),2.03-1.85(m,2H),1.62-1.46(m,2H).

[0159] Example 75 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one Example 75 can also be synthesized by the following method. [ka]

[0160] Step 1 Under nitrogen gas protection, intermediate 1 (1.2 g, 4.91 mmol), 2-fluoro-5-nitro-pyridine (768 mg, 5.40 mmol), and cesium carbonate (2.24 g, 6.88 mmol) were dissolved in acetonitrile (15 mL), and the reaction mixture was heated to 80 °C and stirred for 16 h. Saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried, and concentrated to give the crude product (1S,3S)-N-(5-(difluoromethoxy)pyrimidin-2-yl)-N-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine 75a (1.79 g), 99.45% yield, which was used directly in the next step without further purification. MS m / z(ESI):367.1[M+H] + .

[0161] Step 2 Under a hydrogen gas atmosphere, 75a (1.79 g, 4.89 mmol) and palladium carbon (593 mg, 0.49 mmol, 10% content) were dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (5 mL) and stirred for 5 hours at 20° C. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product N2-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 75b (1.42 g) in 86.40% yield, which was used directly in the next step without further purification. MS m / z(ESI):337.2[M+H] + .

[0162] Step 3 Under nitrogen gas protection, 75b (439 mg, 1.30 mmol) and potassium carbonate (481 mg, 3.48 mmol) were dissolved in N,N-dimethylformamide (7 mL) and stirred at 20 °C for 1 h. After that, the reaction mixture was heated to 55 °C and stirred for 48 h. Saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed, and concentrated. The residue was purified by silica gel column chromatography to give the crude product, which was further separated by reverse-phase HPLC to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 75 (45.2 mg) in 25.88% yield. MS m / z(ESI):454.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.79(d,1H),8.31(d,1H),8.23(s,2H),7.87-7.78(m,1H),7.73(d,1H),7.49(d,1H),7.26- 6.81(m,1H),6.70(d,1H),6.55(d,1H),5.00(s,2H),4.36-4.22(m,2H),2.19-2.03(m,2H),1.97-1.79(m,2H),1.60-1.40(m,2H).

[0163] Example 76 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ka] Example 76 can also be synthesized by the following method.

[0164] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 76, was synthesized according to the synthesis method of Example 75. MS m / z(ESI):454.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.77(d,1H),8.35(d,1H),8.23(s,2H),7.89-7.80(m,1H),7.76-7.69(m,1H),7.47(d,1H),7.2 6-6.82(m,1H),6.71(d,1H),6.55(d,1H),5.03(s,2H),4.38-4.22(m,2H),2.22-2.02(m,2H),1.98-1.78(m,2H),1.62-1.41(m,2H).

[0165] Example 77 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka] Example 77 can also be synthesized by the following method.

[0166] The target product, 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 77, was synthesized according to the synthesis method of Example 75. MS m / z(ESI):454.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.83-8.77(m,1H),8.36(d,1H),8.23(s,2H),8.18-8.10(m,1H),7.90-7.83(m,1H),7.59-7.53(m,1H),7.48(d,1H) ),7.25-6.81(m,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.36-4.22(m,2H),2.19-2.05(m,2H),1.97-1.81(m,2H),1.58-1.42(m,2H).

[0167] Example 78 6''-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one Example 78 can also be synthesized by the following method. [ka]

[0168] Step 1 Under nitrogen gas protection, 3-bromo-5-chloro-1,2,4-thiadiazole (900 mg, 4.51 mmol), cyclopropylboronic acid (775 mg, 9.02 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (164 mg, 0.226 mmol), and potassium carbonate (1.56 g, 11.28 mmol) were dissolved in a mixture of toluene (15 mL), water (5 mL), and ethanol (5 mL), heated to 90° C., and stirred for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 mL). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride (30 mL), dried, filtered, and concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-bromo-5-cyclopropyl-1,2,4-thiadiazole 78a (120 mg) in a yield of 13.0%. 1 H NMR(400MHz,CDCl3)δ2.41(m,1H),1.32(m,2H),1.29(m,2H).

[0169] Step 2 The target product, 6″-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3″-bipyridin]-2-one 78, was synthesized according to the synthesis method of Example 4. MS m / z(ESI):395.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.91(d,1H),7.60(dd,1H),7.47(m,1H),7.41-7.31 (m,2H),6.89(d,1H),6.51(d,1H),6.44(d,1H),6.27(m,1H),4.30-4.25(m, 1H),4.15(m,1H),2.46-2.41(m,1H),2.13-2.06(m,2H),1.93-1.89(m,1H), 1.85-1.81(m,1H),1.55-1.44(m,2H),1.22-1.17(m,2H),1.02-0.98(m,2H).

[0170] Example 82 N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide Example 82 can also be synthesized by the following method. [ka]

[0171] Step 1 Pyridin-2(1H)-one (150 mg, 1.58 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL) at 0 °C. Sodium hydride (69 mg, 1.74 mmol, 60% in mineral oil) was added to the reaction mixture with stirring. After stirring for 10 min, methyl 2-(bromomethyl)benzoate 82a (361 mg, 1.58 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with formic acid (1 mL), concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give methyl 2-((2-oxopyridin-1(2H)yl)methyl)benzoate 82b (310 mg) in 80.8% yield. MS m / z(ESI):244.1[M+H] + .

[0172] Step 2 82b (310 mg, 1.27 mmol) and lithium hydroxide (61 mg, 2.55 mmol) were dissolved in a mixture of methanol (3 mL) and water (1 mL) at room temperature and stirred for 3 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to give the title product 2-(2-oxopyridin-1(2H)yl)methyl)benzoic acid 82c (190 mg) in a 65.0% yield. MS m / z(ESI):230.1[M+H] + .

[0173] Step 3 82c (40 mg, 0.18 mmol), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopenta-1,3-diamine (50 mg, 0.18 mmol), triethylamine (54 mg, 0.54 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature and stirred for 16 h. The reaction mixture was concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain the product N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide 82 (40 mg), yield: 49.3%. MS m / z(ESI):456.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(d,1H),8.23(s,2H),7.75(d,1H),7.41(m,5H),7.03(s,1H),7.01(t ,1H),6.42(d,1H),6.25(d,1H),5.21(s,2H),4.31(m,2H),2.09(m,2H),1.91(t,2H),1.50(m,2H).

[0174] Example 84 6''-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one Example 84 can also be synthesized by the following method. [ka]

[0175] Step 1 Under nitrogen gas protection, 3-iodobenzoic acid (1.5 g, 6.05 mmol), 2-hydroxypyridine (1.15 g, 12.10 mmol), cuprous iodide (576 mg, 3.02 mmol), trans-(1R,2R)-N,N″-dimethyl-1,2-cyclohexanediamine (86 mg, 0.605 mmol), and cesium carbonate (3.94 g, 12.10 mmol) were dissolved in 1″,4-dioxane (30 mL) and heated to 100 °C and stirred for 6 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (elution system A) to give compound 3-(2-oxo-1-pyridyl)benzoic acid 84a (1.2 g) in 92.2% yield. MS m / z(ESI):216.1[M+H] + .

[0176] Step 2 Under nitrogen gas protection, intermediate 1 (70 mg, 0.287 mmol), 84a (93 mg, 0.43 mmol), N,N,N',N''-tetramethylchloroformamidine hexafluorophosphate (121 mg, 0.43 mmol), and N-methylmorpholine (58 mg, 0.573 mmol) were dissolved in acetonitrile (2 mL) and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, filtered, the filtrate was concentrated, and the residue was purified by reverse-phase C18 chromatography (elution system C) to give 6″-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3″-bipyridin]-2-one 84 (79.1 mg), 61.8% yield. MS m / z(ESI):442.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.47(d,1H),8.23(s,2H),7.93(dt,1H),7.89-7.87(m,1H),7.70(dd,1H),7.62-7.52(m,3H),7.48(d,1H),7.0 3(dd,1H),6.51(d,1H),6.35(td,1H),4.47-4.42(m,1H),4.35-4.30(m,1H),2.14-2.06(m,2H),1.95-1.87(m,2H),1.60-1.50(m,2H).

[0177] Example 87 6''-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one Example 87 can also be synthesized by the following method. [ka]

[0178] Step 1 Copper bromide (1.13 g, 5.06 mmol) and tert-butyl nitrite (1.74 g, 16.87 mmol) were dissolved in acetonitrile (5 mL). To the stirred reaction mixture was added 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine 87a (500 mg, 3.37 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then heated to 60 °C and stirred for 0.5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (30 mL), filtered, and the organic phase was washed with water (30 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (eluent C) to give 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine 87b (530 mg) in 74.1% yield. MS m / z (ESI): 214.0 [M + H] + .

[0179] Step 2 Under nitrogen gas protection, 87b (211.8 mg, 1.0 mmol), Intermediate 2 (90 mg, 0.33 mmol), sodium tert-butanol (96.0 mg, 1.0 mmol), tris(dibenzylideneacetone)palladium (61.0 mg, 0.07 mmol), and Ruphos (46.6 mg, 0.1 mmol) were dissolved in 1"4-dioxane (8 mL), heated to 130 °C, and stirred for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6''-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one 87 (30 mg), yield: 22.2%. MS m / z(ESI):402.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.43(d,1H),7.91(d,1H),7.60(dd,1H),7.47(t,1H),7.39(dd,1H),7.16(s,1H),6.91(d,1H),6.69(d,1H),6.56-6.50 (m,2H),6.44(d,1H),6.26(t,1H),4.34-4.29(m,1H),4.20-4.10(m,1H) ,2.34(s,3H),2.25-2.08(m,2H),2.01-1.81(m,2H),1.64-1.41(m,2H).

[0180] Example 88 6''-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one Example 88 can also be synthesized by the following method. [ka]

[0181] Step 1 Copper bromide (1.10 g, 4.93 mmol) and tert-butyl nitrite (1.69 g, 16.43 mmol) were dissolved in acetonitrile (5 mL), and to the stirred reaction mixture was added 6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 88a (500.00 mg, 3.29 mmol). The reaction was stirred at room temperature for 0.5 h, then heated to 60° C. and stirred for 0.5 h. The reaction mixture was concentrated, the residue was diluted with ethyl acetate (100 mL), filtered, the organic phase was washed with water (100 mL), concentrated, the residue was diluted with ethyl acetate (30 mL), filtered, the organic phase was washed with water (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine 88b (490 mg) in a yield of 69.0%. MS m / z(ESI):215.9[M+H] + .

[0182] Step 2 Under nitrogen gas protection, 88b (215.8 mg, 1.0 mmol), Intermediate 2 (90 mg, 0.33 mmol), sodium tert-butanol (96.0 mg, 1.0 mmol), tris(dibenzylideneacetone)palladium (61.0 mg, 0.07 mmol), and Ruphos (46.6 mg, 0.1 mmol) were dissolved in 1"4-dioxane (8 mL) and heated to 130 °C and stirred for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6''-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one 88 (10.5 mg), yield: 7.23%. MS m / z(ESI):406.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.96-8.90(m,1H),7.91(d,1H),7.59(d,1H),7.54-7.44(m,2H),7.43-7.37(m,2H),6.91(d,1H),6.71(d,1 H),6.60-6.40(m,2H),6.27(t,1H),4.38-4.26(m,1H),4.23-4.10(m,1H),2.25-2.05(m,2H),2.01-1.81(m,2H),1.65-1.40(m,2H).

[0183] Example 91 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidine Example 91 can also be synthesized by the following method. [ka]

[0184] Step 1 Under nitrogen gas protection, 2-fluoro-5-iodopyridine 91a (300 mg, 1.35 mmol), 1,1-dioxoisothiazolidine (326 mg, 2.69 mmol), cuprous iodide (51 mg, 0.27 mmol), dimethylethylenediamine (24 mg, 0.27 mmol), and potassium carbonate (558 mg, 4.04 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 130 °C in a microwave oven with stirring for 1 h. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL × 2). The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give 2-(6-fluoropyridin-3-yl)-1,1-dioxoisothiazolidine 91b (269 mg) in 92.47% yield. MS m / z(ESI):217.1[M+H] + .

[0185] Step 2 Under nitrogen gas protection, intermediate 1 (75 mg, 0.31 mmol), 91b (133 mg, 0.62 mmol), and diisopropylethylamine (80 mg, 0.62 mmol) were dissolved in dimethyl sulfoxide (1 mL), and the reaction mixture was heated to 125° C. and stirred for 48 h. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (ammonium bicarbonate system) to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidine 91 (17.1 mg) in a 12.59% yield. MS m / z(ESI):441.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.87(d,1H),7.49(d,1H),7.41-7.31(m,1H),7.25-6.80(m,1H),6.74(d,1H),6.48(d,1H), 4.36-4.16(m,2H),3.59(t,2H),3.42-3.36(m,2H),2.40-2.29(m,2H),2.16-2.04(m,2H),1.93-1.76(m,2H),1.59-1.38(m,2H).

[0186] Example 92 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butanesultam [ka] Example 92 can also be synthesized by the following method.

[0187] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butanesultam 92, was synthesized according to the synthesis method of Example 91. MS m / z (ESI): 455.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.88(d,1H),7.46(d,1H),7.36-7.28(m,1H),7.23-6.81(m,1H),6.76(d,1H),6.44( d,1H),4.35-4.18(m,2H),3.57-3.46(m,2H),3.28-3.18(m,2H),2.18-2.03(m,4H),1.95-1.69(m,4H),1.59-1.38(m,2H).

[0188] Example 93 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Example 93 can also be synthesized by the following method. [ka]

[0189] Step 1 To a solution of 57b (167 mg, 0.73 mmol) and iodomethane (517 mg, 3.64 mmol) in tetrahydrofuran (3 mL) was added lithium bistrimethylsilylamide (1 M, 3.6 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. Saturated ammonium chloride solution was added to the reaction mixture at 0 °C. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography to give 6-(6-fluoropyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 93a (110 mg) in 58.69% yield. MS m / z(ESI):258.1[M+H] + .

[0190] Step 2 Under nitrogen gas protection, intermediate 1 (100 mg, 0.41 mmol), 93a (70 mg, 0.27 mmol), and diisopropylethylamine (106 mg, 0.82 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction mixture was heated to 130 °C and stirred for 48 h. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 93 (32.1 mg) in 24.50% yield. MS m / z (ESI): 482.3 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.79-8.69(m,1H),8.29-8.19(m,3H),7.86(d,1H),7.68-7.59(m,1H),7.49(d,1H),7.32-7.26(m,1H) ),7.23-6.82(m,1H),6.90(d,1H),6.57(d,1H),4.42-4.20(m,2H),2.23-2.03(m,2H),2.01-1.78(m,2H),1.64-1.34(m,8H).

[0191] Example 95 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione Example 95 can also be synthesized by the following method. [ka]

[0192] Step 1 75b (75 mg, 0.22 mmol), 2,3-pyridinedicarboxylic anhydride (33 mg, 0.22 mmol), and 4-dimethylaminopyridine (3 mg, 0.02 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at 50 °C for 1 hour. To the reaction mixture was added acetic anhydride (46 mg, 0.45 mmol), and the mixture was heated to 70 °C and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione 95 (21.3 mg) in 20.44% yield. MS m / z(ESI):468.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07-8.99(m,1H),8.42-8.33(m,1H),8.24(s,2H),7.98(d,1H),7.89-7.79(m,1H),7.51(d,1H),7.44-7.3 8(m,1H),7.26-6.81(m,1H),6.98(d,1H),6.57(d,1H),4.38-4.26(m,2H),2.2-2.07(m,2H),1.95-1.83(m,2H),1.60-1.44(m,2H).

[0193] Example 97 1-Cyclopropyl-3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one [ka] Example 97 can also be synthesized by the following method.

[0194] The target product, 1-cyclopropyl-3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 97, was synthesized according to the synthesis method of Example 56. MS m / z (ESI): 496.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.09(d,1H),8.00(d,1H),7.90(d,1H),7.56-7.45(m,2H),7.26-6.80(m,1H),6.96(d,1H), 6.58(d,1H),4.40-4.21(m,2H),3.10-2.96(m,1H),2.22-2.03(m,2H),2.00-1.81(m,2H),1.61-1.42(m,2H),1.16-0.95(m,4H).

[0195] Example 99 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile Example 99 can also be synthesized by the following method. [ka]

[0196] Step 1 Under nitrogen gas protection, 7-bromopyrazole[1,5-a]pyridine 99a (650 mg, 3.3 mmol), (6-fluoropyridin-3-yl)boronic acid (604 mg, 4.29 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (241 mg, 0.33 mmol), and potassium carbonate (1.14 g, 8.25 mmol) were dissolved in a mixture of 1,4-dioxane (16 mL) and water (4 mL). The reaction mixture was heated to 100 °C and stirred for 10 h. The reaction mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by silica gel column chromatography (eluent system B) to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine 99b (640 mg) in 91.0% yield. MS m / z(ESI):214.1[M+H] + .

[0197] Step 2 99b (300 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (5 mL) and placed in an ice-water bath. Under nitrogen gas protection, phosphorus oxychloride (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (20 mL), and aqueous sodium hydroxide was added to adjust the pH to slightly alkaline. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride (30 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (eluent system B) to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde 99c (310 mg) in 91.3% yield. MS m / z (ESI): 242.1 [M + H] + .

[0198] Step 3 99c (200 mg, 0.83 mmol) and hydroxylamine hydrochloride (86 mg, 1.24 mmol) were dissolved in a mixture of ethanol (15 mL) and water (5 mL), and the reaction was heated to 50° C. and stirred for 2 h. The reaction was concentrated, saturated aqueous sodium bicarbonate (10 mL) was added, filtered, and the filter cake was washed with water and dried to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine-3-formaldoxime 99d (150 mg) in 70.6% yield. MS m / z(ESI):257.1[M+H] + .

[0199] Step 4 99d (60 mg, 0.234 mmol) was dissolved in acetic anhydride (5 mL), and the reaction was heated to 130° C. and stirred for 2 h. The reaction was cooled to room temperature, filtered, and the filter cake was washed with saturated aqueous sodium bicarbonate and water solutions, respectively, and dried to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine-3-cyano 99e (30 mg), 53.8% yield. MS m / z(ESI):239.1[M+H] + .

[0200] Step 5 99e (35 mg, 0.147 mmol), Intermediate 2 (36 mg, 0.147 mmol), and diisopropylethylamine (40 mg, 0.294 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 16 h. The reaction was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile 99 (32 mg) in 47.1% yield. MS m / z(ESI):463.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.55(d,1H),8.24(s,2H),8.00 (dd,1H),7.82(dd,1H),7.67(dd,1H),7.50(d,1H),7.30(dd,1H),7.21(s,1H),7.03(t,1H) ,6.60(d,1H),4.42-4.29(m,2H),2.21-2.07(m,2H),2.03-1.86(m,2H),1.60-1.46(m,2H).

[0201] Example 102 (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-fluoropyrazole[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine Example 102 can also be synthesized by the following method. [ka]

[0202] Step 1 (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(pyrazole[1,5-a]pyridin-7-yl)pyridin-2yl)cyclopentane-1,3-diamine 52 (30 mg, 0.068 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) (24 mg, 0.068 mmol) were dissolved in acetonitrile (2 mL), and the reaction was stirred at room temperature for 1 h. The reaction was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give the desired product (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-fluoropyrazole[1,5-a]pyridin-7-yl)pyridin-2yl)cyclopentane-1,3-diamine 102 (7 mg) was obtained, with a yield of 22.4%. MS m / z(ESI):456.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.53(d,1H),8.24(s,2H),8.11(d,1H),7.98(dd,1H),7.60(dd,1H),7.49(d,1H),7.27(dd,1H),7.10 (d,1H),7.03(t,1H),6.98(dd,1H),6.58(d,1H),4.40-4.28(m,2H),2.22-2.07(m,2H),2.03-1.85(m,2H),1.60-1.46(m,2H).

[0203] Example 108 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one Example 108 can also be prepared by the following method. [ka]

[0204] Step 1 Under nitrogen gas protection, intermediate 1 (300 mg, 1.23 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (301.4 mg, 1.35 mmol), and N,N-diisopropylethylamine (476.3 mg, 3.68 mmol) were dissolved in dimethyl sulfoxide (3 mL), heated to 130 °C, and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (formic acid system) to give (6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid 108a (250 mg) in a 55.7% yield. MS m / z(ESI):366.2[M+H]+.

[0205] Step 2 Under nitrogen gas protection, 108a (80 mg, 0.22 mmol), 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (98.6 mg, 0.44 mmol), [1,1″-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (15.9 mg, 0.024 mmol), and sodium carbonate (71.0 mg, 0.66 mmol) were dissolved in a mixture of 1″4-dioxane (5 mL) and water (0.5 mL), heated to 100° C., and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 108 (39 mg), the yield was 37.1%. MS m / z (ESI): 466.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.56(s,1H),8.46(d,1H),8.24(s,2H),7.95-7.84(m,2H),7.72(d,1H),7.49(d,1H),7.3 9(t,1H),7.03(s,1H),6.79(s,1H),6.55(d,1H),4.40-4.26(m,2H),2.22-2.04(m,2H),1.97-1.82(m,2H),1.59-1.45(m,2H).

[0206] Example 112 6''-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3''-bipyridin]-2-one [ka]

[0207] Following the synthesis method of Example 27, 6″-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3″-bipyridin]-2-one 112 was obtained. MS m / z(ESI):422.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.62(d,1H),7.91(d,1H),7.59(dd,1H),7.54(d,1H),7.50-7.43(m,1H),7.39(dd,1H),6.96-6.88(m,2H),6.83(d, 1H),6.52(d,1H),6.44(d,1H),6.27(t,1H),4.39-4.26(m,1H),4.21- 4.09(m,1H),2.23-2.06(m,2H),2.00-1.81(m,2H),1.62-1.43(m,2H).

[0208] Example 113 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0209] Under nitrogen gas protection, 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine 113a (77 mg, 0.29 mmol), Intermediate 2 (60 mg, 0.22 mmol), sodium tert-butanol (64 mg, 0.67 mmol), tris(dibenzylideneacetone)dipalladium (41 mg, 0.04 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41 mg, 0.09 mmol) were dissolved in 1,4-dioxane (2 mL), heated to 130 °C in a microwave oven, and stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 113 (31.7 mg), 31.4% yield. MS m / z(ESI):456.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.83(d,1H),7.92(s,1H),7.86(s,1H),7.60(d,1H),7.52-7.44(m,1H),7.40(d,1H),7.15(d,1H),7.05(d,1H),6.94( d,1H),6.53(d,1H),6.44(d,1H),6.27(t,1H),4.40-4.29(m,1H),4.27 -4.12(m,1H),2.22-2.09(m,2H),2.03-1.82(m,2H),1.66-1.43(m,2H).

[0210] Example 114 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridin]-2-one Example 114 can also be prepared by following the procedure below. [ka]

[0211] Step 1 Under nitrogen gas protection, 63c (241 mg, 0.67 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (259 mg, 1.35 mmol), and cuprous iodide (192 mg, 1.01 mmol) were dissolved in N,N-dimethylformamide (3 mL), heated to 90 °C in a microwave oven, and stirred for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL) and saturated sodium chloride (20 mL). The organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the title product tert-butyl (1S,3S)-3-(((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate 114a (160 mg) in a 68.5% yield. MS m / z (ESI): 348.2 [M + H] + .

[0212] Step 2 The target product (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 114b was synthesized according to the synthesis method of Step 4 of Example 63. MS m / z (ESI): 296.2 [M + H] + .

[0213] Step 3 The target product, 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridin]-2-one 114, was synthesized according to the synthesis method of Step 5 of Example 63. MS m / z(ESI):418.2[M+H] + . 1H NMR(400MHz,CD3OD)δ8.52(s,1H),7.95(d,1H),7.60(m,2H),7.45(m,1H),6.62(m, 2H),6.46(m,1H),4.62(d,1H),4.39(m,1H),2.29(m,2H),2.11(m,2H),1.68(m,2H)

[0214] Example 115 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0215] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one, was synthesized according to the synthesis method of Example 75. MS m / z(ESI):468.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.64(d,1H),8.37(d,1H),8.23(s,2H),7.86(dd,1H),7.55(d,1H),7.48(d,1H),7.03(t,1H),6.71( d,1H),6.55(d,1H),4.98(s,2H),4.33-4.26(m,2H),2.57(s,3H),2.18-2.08(m,2H),1.95-1.82(m,2H),1.58-1.44(m,2H).

[0216] Example 116 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0217] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one, was synthesized according to the synthesis method of Example 75. MS m / z(ESI):468.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.34(d,1H),8.23(s,2H),7.85(dd,1H),7.59(s,1H),7.49(d,1H),7.03(t,1H),6.72( d,1H),6.54(d,1H),4.97(s,2H),4.33-4.26(m,2H),2.60(s,3H),2.18-2.08(m,2H),1.95-1.82(m,2H),1.58-1.45(m,2H).

[0218] Example 117 (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-methylpyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine Example 117 can also be prepared by following the procedure below. [ka]

[0219] Step 1 99c (300 mg, 1.24 mmol) was dissolved in methanol (10 mL) under ice bath, and sodium borohydride (47 mg, 1.24 mmol) was added to the reaction mixture while stirring. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with hydrochloric acid (1 M). The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent system B) to give (7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol 117a (240 mg) in 79.3% yield. MS m / z(ESI):244.1[M+H] + .

[0220] Step 2 117a (50 mg, 0.206 mmol), phenyl chlorothioformate (35.5 mg, 0.206 mmol), and 4-dimethylaminopyridine (50.2 mg, 0.412 mmol) were dissolved in acetonitrile (5 mL), and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give oxy-((7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methyl)oxy-phenyl thiocarbonate 117b (30 mg) in 64.1% yield. MS m / z(ESI):380.1[M+H] + .

[0221] Step 3 Under nitrogen gas protection, 117b (50 mg, 0.132 mmol), azodiisobutyronitrile (4.3 mg, 0.026 mmol), and tributyltin hydride (4.3 mg, 0.026 mmol) were dissolved in toluene (3 mL), heated to 130 °C, and stirred for 1 h. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give 7-(6-fluoropyridin-3-yl)-3-methylpyrazolo[1,5-a]pyridine 117c (20 mg) in a 66.8% yield.

[0222] Step 4 117c (20 mg, 0.088 mmol), intermediate 2 (21.5 mg, 0.088 mmol), and diisopropylethylamine (22.7 mg, 0.176 mmol) were dissolved in dimethyl sulfoxide (2 mL), heated to 130 °C, and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give the target product (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-methylpyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 117 (12 mg) was obtained, with a yield of 30.2%. MS m / z(ESI):452.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.55(d,1H),8.24(s,2H),8.02(dd,1H),7.83(s,1H),7.54(dd,1H),7.50(d,1H),7.21(dd,1H),7.05(t,1H) ,7.03(s,1H),6.90(dd,1H),6.57(d,1H),4.40-4.30(m,2H),2.30(s,3H),2.18-2.10(m,2H),1.97-1.85(m,2H),1.58-1.49(m,2H).

[0223] Example 118 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-cyano [ka]

[0224] The target product, 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-cyano, was synthesized according to the synthesis method of Example 99. MS m / z(ESI):464.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.95(d,1H),8.84(s,1H),8.76(d,1H),8.27(dd,1H),8.24(s,2H),7.62(d,1H),7.56(d,1H) ,7.52(d,1H),7.04(t,1H),6.65(d,1H),4.44-4.30(m,2H),2.23-2.08(m,2H),1.99-1.86(m,2H),1.59-1.51(m,2H).

[0225] Example 119 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide Example 119 can also be prepared by following the procedure below. [ka]

[0226] Step 1 Under nitrogen gas protection, 1,2-thiazolidine-1,1-dioxide (2 g, 16.5 mmol) and 4-methoxybenzyl chloride (3.10 g, 19.8 mmol) were dissolved in tetrahydrofuran (35 mL) at 0 °C. Sodium hydride (792 mg, 19.8 mmol, content: 60%) was added portionwise to the reaction mixture while stirring. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent system A) to give 2-(4-methoxybenzyl)isothiazolidine-1,1-dioxide 119b (1.52 g) in a 38% yield. MS m / z (ESI): 505.1 [2M + Na] + .

[0227] Step 2 119b (1 g, 4.14 mmol) was dissolved in tetrahydrofuran (35 mL), and butyllithium (2.5 M, 4.14 mL) was added dropwise to the reaction mixture at −78° C. After stirring for 1 hour at −78° C., iodomethane (3.53 g, 24.9 mmol) was added dropwise to the reaction mixture. After stirring for 2 hours at −78° C., the reaction mixture was transferred to room temperature and stirred for 1 hour. The reaction mixture was purified by preparative HPLC (formic acid system) to give 2-(4-methoxybenzyl)-5,5-dimethylisothiazolidine-1,1-dioxide 119c (586 mg), yield 52%. MS m / z(ESI):539.2[2M+H] + .

[0228] Step 3 119c (0.32 g, 1.19 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise to the reaction mixture with stirring. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, diluted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride, dried, and concentrated to give 5,5-dimethylisothiazolidine-1,1-dioxide 119d (165 mg). The product was used directly in the next step without further purification. MS m / z(ESI):150.1[M+H] +

[0229] Step 4 Following the synthesis method of Step 1 of Example 91, 2-(6-fluoropyridin-3-yl)-5,5-dimethylisothiazolidine 1,1-dioxide 119e (154 mg) was obtained in a yield of 56%. MS m / z(ESI):245.1[M+H] + .

[0230] Step 5 The target product 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide 119 (21 mg) was obtained in a 14% yield by following the synthesis method of Step 2 of Example 91. MS m / z (ESI): 469.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.88(d,1H),7.46(d,1H),7.35(dd,1H),7.03(t,1H),6.72(d,1H),6.48( d,1H),4.26(dp,2H),3.53(t,2H),2.21(t,2H),2.10(dtd,2H),1.85(qt,2H),1.58-1.42(m,2H),1.39(s,6H).

[0231] Example 120 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,6-dimethyl-1,2-thiazinane-1,1-dioxide [ka]

[0232] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,6-dimethyl-1,2-thiazinane-1,1-dioxide 120, was synthesized according to the synthesis method of Example 91. MS m / z (ESI): 483.2 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.85(d,1H),7.47(d,1H),7.28(dd,1H),7.03(t,1H),6.74(d,1H),6.43(d, 1H),4.27(dp,2H),3.50(t,2H),2.10(pd,2H),2.05-1.96(m,2H),1.88-1.76(m,4H),1.49(ddd,2H),1.39(s,6H).

[0233] Example 121 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-2,3-dihydroisothiazole[5,4-b]pyridine 1,1-dioxide Example 121 can also be obtained in the following manner. [ka]

[0234] Step 1 2-Aminosulfonyl-N,N-dimethylnicotinamide (4 g, 17.45 mmol), benzyltriethylammonium chloride (40 mg, 0.174 mmol), and sodium carbonate (1.85 g, 17.45 mmol) were dissolved in purified water (2 mL), heated to 60 °C, and stirred for 5 h. The reaction mixture was concentrated to half its volume, and then diluted with dilute hydrochloric acid (1 N, 100 mL) to precipitate a large amount of solid. The solid was filtered and dried to give isothiazolo[5,4-b]pyridin-3(2H)-one 1,1-dioxide 121a (1.27 g) in 40% yield. MS m / z(ESI):185.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.04(dd,1H),8.45(dd,1H),7.93(dd,1H).

[0235] Step 2 Under nitrogen gas protection, 121a (194 mg, 1.05 mmol) was dissolved in tetrahydrofuran (4 mL). A solution of lithium aluminum hydride (88 mg, 2.32 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 2 h. After dilution with ethyl acetate (25 mL), the organic phase was washed with saturated ammonium chloride (10 mL), dried, and concentrated to give 2,3-dihydroisothiazole[5,4-b]pyridine 1,1-dioxide 121b (150 mg). The product was directly used in the next step without further purification. MS m / z (ESI): 171.0 [M + H] + .

[0236] Step 3 Under nitrogen gas protection, 2-fluoro-5-iodopyridine (120 mg, 0.54 mmol), 121b (92 mg, 0.54 mmol), cuprous iodide (123 mg, 0.65 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (92 mg, 0.65 mmol), and potassium carbonate (260 mg, 1.88 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 4 h. After filtering the reaction mixture, the filtrate was diluted with ethyl acetate (25 mL) and water (10 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL × 2). The combined organic phase was washed with saturated sodium chloride (25 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 2-(6-fluoropyridin-3-yl)-2,3-dihydroisothiazole[5,4-b]pyridine 1,1-dioxide 121c (36 mg), yield 25%. MS m / z(ESI):266.1[M+H] + .

[0237] Step 4 Intermediate 1 (32 mg, 0.13 mmol), 121c (35 mg, 0.13 mmol), and N,N-diisopropylethylamine (51 mg, 0.39 mmol) were dissolved in dimethyl sulfoxide (1 mL), heated to 125 °C, and stirred for 16 h. The reaction mixture was purified by preparative HPLC (formic acid system) to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-2,3-dihydroisothiazole[5,4-b]pyridine 1,1-dioxide 121 (6 mg) in a 9% yield. MS m / z(ESI):490.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ8.87-8.77(m,1H),8.18(q,3H),7.90-7.83(m,1H),7.67(dd,1H),7.59(dd,1H),6.41(t,1H),6.47(d,1H) ),5.26(d,1H),5.04(s,1H),4.74(s,2H),4.43(p,1H),4.25(s,1H),2.42-2.28(m,2H),2.12-2.02(m,2H),1.58-1.47(m,2H).

[0238] Example 122 and Example 123 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and 6-(6-(((1S,3S)-3-((5-(bromodifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka]

[0239] Step 1 Thiophosgene (6.61 g, 57.46 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine 122a (5.00 g, 38.30 mmol) and diisopropylethylamine (7.43 g, 57.46 mmol) in dichloromethane (100 mL) under ice bath pressure, and the reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was cooled in an ice bath, and sodium ethylthiolate (6.44 g, 76.61 mmol) was added to the reaction, and the reaction was stirred under ice bath pressure for 1 h. The reaction was filtered, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give the title product O-(2-chloropyrimidin-5-yl)S-dithiocarbonylethyl 122b (4.20 g) in 46.7% yield. MS m / z(ESI):235.0[M+H] + .

[0240] Step 2 A solution of hydrogen fluoride in pyridine (40 mL, containing 70% hydrofluoric acid) was added dropwise to a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (4.87 g, 17.04 mmol) in dichloromethane (100 mL) at -78 °C, and the reaction was stirred for 30 minutes. A solution of 122b (1.00 g, 4.26 mmol) in dichloromethane (5 mL) was added dropwise to the reaction, and the reaction was warmed to 0 °C and stirred for 2 hours. The pH of the reaction was adjusted to 9 with aqueous sodium carbonate, the organic phase was separated and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give a mixture of the products 2-chloro-5-(trifluoromethoxy)pyrimidine 122c and 5-(bromodifluoromethoxy)-2-chloropyrimidine 123a (160 mg). 122c MS m / z(ESI):199.0[M+H] + . 123a MS m / z(ESI):259.0[M+H] + .

[0241] Step 3 6-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridyl]-7H-pyrrolo[3,4-b]pyridin-5-one (31 mg, 0.10 mmol, see Example 75 for its synthesis), a mixture of 122c and 123a (40 mg), and diisopropylethylamine (26 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 60° C. and stirred for 16 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 122 (6 mg), yield 12.6%. MS m / z (ESI): 472.2 [M + H] + . 1 H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.85(d,1H),7.59(dd ,1H),6.63(d,1H),4.96(s,2H),4.40(m,1H),4.32(t,1H),2.28(m,2H),2.00(m,2H),1.61(m,2H).

[0242] 6-(6-(((1S,3S)-3-((5-(bromodifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 123 (16 mg) was obtained in a yield of 29.8%. MS m / z(ESI):532.1[M+H] + . 1H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.84(dd,1H),7.59(d d,1H),6.63(d,1H),4.96(s,2H),4.41(m,1H),4.30(m,1H),2.27(dd,2H),2.02(m,2H),1.60(m,2H)

[0243] Example 124 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka]

[0244] Step 1 122a (1.00 g, 7.66 mmol), cesium carbonate (3.24 g, 9.96 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.31 g, 9.96 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred for 16 h at room temperature. Ethyl acetate (160 mL) was added to the reaction mixture, and the organic phase was washed with water (25 mL) and saturated sodium chloride (25 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (eluent system B) to give 2-chloro-5-(2,2,2-trifluoroethoxy)pyrimidine 124a (1.20 g) in 73.7% yield. MS m / z(ESI):213.0[M+H] + .

[0245] Step 2 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 124 was synthesized. MS m / z (ESI): 486.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.80(dd,1H),8.36(d,1H),8.20(s,2H),8.15(dd,1H),7.87(dd,1H),7.56(dd,1H),7.10 (d,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.71(q,2H),4.28(q,2H),2.12(m,2H),1.91(m,2H),1.49(m,2H).

[0246] Example 125 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0247] Step 1 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 125 was synthesized. MS m / z (ESI): 486.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.35(d,1H),8.20(s,2H),8.11(dd,1H),7.87(dd,1H),7.62(dd,1H),7.10 (d,1H),6.69(d,1H),6.55(d,1H),4.93(s,2H),4.71(q,2H),4.28(d,2H),2.11(d,2H),1.90(m,2H),1.49(m,2H).

[0248] Example 126 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0249] The target product, 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 126, was synthesized according to the synthesis method of Example 75. MS m / z(ESI):429.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.18(s,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H),7.54(s,1H),6.71(d, 1H),6.56(d,1H),4.93(s,2H),4.36-4.28(m,2H),2.17-2.12(m,2H),2.08-1.85(m,3H),1.59-1.47(m,2H),0.98-0.84(m,4H).

[0250] Example 127 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0251] Step 1 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 127 was synthesized. MS m / z(ESI):428.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.34(d,1H),8.11(dd,1H),8.07(s,2H),7.87(dd,1H),7.62(dd,1H),7.01(d,1H),6.68( d,1H),6.55(d,1H),4.93(s,2H),4.29(dd,2H),2.10(m,2H),1.90(m,2H),1.73(m,1H),1.50(m,2H),0.83(m,2H),0.59(m,2H).

[0252] Example 128 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka]

[0253] Step 1 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 128 was synthesized. MS m / z(ESI):428.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.80(dd,1H),8.36(d,1H),8.14(dd,1H),8.06(s,2H),7.87(dd,1H),7.56(dd,1H),7.00(d,1H),6.65 (d,1H),6.54(d,1H),4.97(s,2H),4.29(m,2H),2.07(m,2H),1.86(m,2H),1.72(m,1H),1.49(m,2H),0.82(m,2H),0.59(m,2H).

[0254] Example 129 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0255] Step 1 Under nitrogen gas protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 129a (500 mg, 2.31 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (510 mg, 2.55 mmol), cesium carbonate (1.51 g, 4.63 mmol), tris(dibenzylideneacetone)dipalladium (424 mg, 0.46 mmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL) and heated to 130 °C in a microwave oven for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) and preparative HPLC (formic acid system) to give tert-butyl N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate 129b (240 mg), yield: 30.9%. MS m / z (ESI): 336.0 [M + H] + .

[0256] Step 2 129b (202 mg, 0.60 mmol) was dissolved in methanol (2 mL) at room temperature and stirred. A solution of hydrochloric acid in 1,4-dioxane (4 M, 5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (aqueous ammonia system) to give (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 129c (140 mg) in a 98.6% yield. MS m / z (ESI): 236.2 [M + H] + .

[0257] Step 3 129c (150 mg, 0.64 mmol), 2-fluoro-5-nitro-pyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL), and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give (1S,3S)-N-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine 129d (190 mg) in 83.4% yield. MS m / z(ESI):358.1[M+H] + .

[0258] Step 4 129d (190 mg, 0.53 mmol) and palladium carbon (28 mg, 0.026 mmol, content: 10%) were dissolved in methanol (5 mL) and stirred for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give N-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 129e (170 mg) in a 97.7% yield. MS m / z(ESI):328.1[M+H] + .

[0259] Step 5 129e (80 mg, 0.24 mmol), methyl 3-(bromomethyl)pyridinecarboxylate (62 mg, 0.27 mmol), and potassium carbonate (101.2 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred for 1 hour. The mixture was then heated to 50 °C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 129 (24.3 mg) in a 22.4% yield. MS m / z(ESI):445.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.66(t,1H),8.35 (d,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H),7.27(dd,1H),6.86(td,1H),6.75(d,1H),6.70(d,1H),6.56(d, 1H),4.93(s,2H),4.38-4.24(m,1H),4.22-4.09(m,1H),2.24-2.10(m,2H),2.03-1.82(m,2H),1.66-1.39(m,2H).

[0260] Example 130 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0261] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 130 was synthesized. MS m / z(ESI):441.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.44(d,1H),8.35(d,1H),8.14-8.08(m,1H),7.88(dd,1H),7.61(dd,1H),7.16(dd,1H),6.69(dd,2H) ),6.54(t,2H),4.93(s,2H),4.34-4.22(m,1H),4.20-4.07(m,1H),2.34(s,3H),2.21-2.06(m,2H),2.00-1.81(m,2H),1.63-1.39(m,2H).

[0262] Example 131 6-(6-(((1S,3S)-3-((4-methylquinazolin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0263] Step 1 The target product, 6-(6-(((1S,3S)-3-((4-methylquinazolin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 131, was synthesized according to the synthesis method of Step 3 of Example 122. MS m / z(ESI):452.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.11(d,1H),7.89(m,2H),7.62( dd,2H),7.40(dd,2H),7.19(d,1H),6.72(d,1H),6.57(d,1H),4.93(s,2H),4.50(m 1H),4.31(m,1H),2.70(s,3H),2.16(m,2H),1.94(m,2H),1.54(m,2H).

[0264] Example 132 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one Example 132 can also be prepared by following the procedure below. [ka]

[0265] Step 1 75b (57.7 mg, 0.25 mmol) and potassium carbonate (73.9 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature and stirred for 1 hour. The mixture was then heated to 60 °C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 132 (21 mg) in a 25.9% yield. MS m / z(ESI):455.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.89-8.75(m,2H),8.40(d,1H),8.23(s,2H),7.91(dd,1H),7.48(d,1H),7.03(t,1H),6. 74(d,1H),6.56(d,1H),5.02(s,2H),4.36-4.23(m,2H),2.21-2.05(m,2H),1.98-1.81(m,2H),1.62-1.43(m,2H).

[0266] Example 133 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka]

[0267] Following the synthesis method of Example 75, 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 133 was synthesized. MS m / z(ESI):456.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.61(d,2H),8.37(d,1H),8.20(d,1H),8.15(d,1H),7.88(dd,1H),7.56(dd,1H) ,6.70(d,1H),6.56(d,1H),4.97(s,2H),4.47-4.28(m,2H),2.18-2.10(m,2H),1.98-1.85(m,2H),1.62-1.48(m,2H).

[0268] Example 134 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0269] Following the synthesis method of Example 75, 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 134 was synthesized. MS m / z(ESI):456.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.61(d,2H),8.35(d,1H),8.21(d,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H) ,6.72(d,1H),6.56(d,1H),4.93(s,2H),4.45-4.28(m,2H),2.18-2.10(m,2H),1.98-1.85(m,2H),1.62-1.48(m,2H).

[0270] Example 135 6'-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one [ka]

[0271] Following the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 135 was obtained. MS m / z(ESI):428.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.40(d,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd,1H),7.39(dd,1H),7.07(d,1H),6.91(d,1H),6.59- 6.49(m,3H),6.44(dt,1H),6.26(td,1H),4.36-4.25(m,1H),4.20-4.08(m,1H),2.20-2.07(m,2H),2.02-1.81(m,3H),1.61-1.4 (m,2H),1.07-0.98(m,2H),0.84-0.74(m,2H).

[0272] Example 136 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0273] The target product, 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 136, was synthesized according to the synthesis method of Example 75. MS m / z (ESI): 472.1 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.32(d,1H),8.23(s,2H),8.09(dd,1H),7.84(dd,1H),7.48(d,1H),7.03(dd,1H ),6.71(d,1H),6.55(d,1H),4.93(s,2H),4.26-4.33(m,2H),2.07-2.17(m,2H),1.83-1.93(m,2H),1.46-1.56(m,2H).

[0274] Example 137 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka]

[0275] The target product, 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 137, was synthesized according to the synthesis method of Example 75. MS m / z (ESI): 472.1 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.82(dd,1H),8.36(d,1H),8.23(s,2H),8.11(dd,1H),7.86(dd,1H),7.48(d,1H),7.03(dd,1H ),6.70(d,1H),6.55(d,1H),4.96(s,2H),4.26-4.33(m,2H),2.07-2.15(m,2H),1.83-1.93(m,2H),1.47-1.56(m,2H).

[0276] Example 138 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-trifluoromethyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0277] The target product, 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-trifluoromethyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 138, was synthesized according to the synthesis method of Example 75. MS m / z (ESI): 522.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.36(d,1H),8.23(s,2H),8.16(d,1H),7.86(dd,1H),7.48(d,1H),7.03(t,1H) ,6.77(d,1H),6.57(d,1H),5.13(s,2H),4.33-4.27(m,2H),2.19-2.05(m,2H),1.97-1.81(m,2H),1.56-1.46(m,2H).

[0278] Example 139 (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine [ka]

[0279] Following the synthesis method of Example 52, (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine 139 was synthesized. MS m / z(ESI):439.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.88-8.80(m,2H),8.53(s,1H),8.23(s,2H),8.21-8.16(m,1H),7.83(dd,1H),7.49(d,1H),7.26-7.2 1(m,1H),7.03(t,1H),6.98(d,1H),6.60(dd,1H),4.41-4.26(m,2H),2.24-2.07(m,2H),2.01-1.82(m,2H),1.62-1.44(m,2H).

[0280] Example 140 (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine [ka]

[0281] Following the synthesis method of Example 52, (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine 140 was synthesized. MS m / z(ESI):439.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(d,1H),8.51(s,1H),8.24(s,2H),8.08(dd,1H),7.77-7.66(m,2H),7.50(d,1H),7.31(dd, 1H),7.21(d,1H),7.03(t,1H),6.61(d,1H),4.45-4.26(m,2H),2.23-2.08(m,2H),2.00-1.84(m,2H),1.62-1.44(m,2H).

[0282] Example 142 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0283] Following the synthesis method of Example 122, 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 142 was synthesized. MS m / z(ESI):532.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.40(s,2H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.74(dd,1H),7.61(dd,1H ),6.69(d,1H),6.55(d,1H),4.93(s,2H),4.33-4.30(m,2H),2.16-2.10(m,2H),1.93-1.86(m,2H),1.56-1.51(m,2H).

[0284] Example 143 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0285] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 143 was obtained. MS m / z(ESI):495.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.83(d,1H),8.75(dd,1H),8.35(d,1H),8.15-8.06(m,1H),7.88(dd,1H),7.86(s,1H),7.62(dd,1H),7.15(dd ,1H),7.04(d,1H),6.71(s,1H),6.57(d,1H),4.93(s,2H),4.36-4.15(m,2H),2.23-2.10(m,2H),2.05-1.83(m,2H),1.65-1.42(m,2H).

[0286] Example 144 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Example 144 can also be prepared by following the procedure below. [ka]

[0287] Step 1 tert-Butyl nitrite (14.73 g, 142.87 mmol) was added dropwise to a solution of 6-bromo-1,2,4-triazin-3-amine 144a (5.00 g, 28.57 mmol) in acetonitrile (50 mL) and dimethyl disulfide (10 mL) at room temperature, and the mixture was stirred for 3 h. The reaction mixture was quenched with methanol (515 mL), the organic phase was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to give the title product 6-bromo-3-(methylthio)-1,2,4-triazine 144b (4.60 g) in 78.1% yield. MS m / z(ESI):205.9[M+H] + .

[0288] Step 2 Under nitrogen gas protection, 144b (2.00 g, 9.71 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (5.59 g, 29.17 mmol), and cuprous iodide (5.55 g, 29.12 mmol) were dissolved in N,N-dimethylformamide (15 mL), heated to 90 °C, and stirred for 3 h. The reaction mixture was diluted with ethyl acetate (180 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 3-(methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (710 mg) in a 37.5% yield. MS m / z (ESI): 196.0 [M + H] + .

[0289] Step 3 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 144 was synthesized. MS m / z(ESI):457.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.10,8.60(d,1H),8.75(m,1H),8.70(s,1H),8.36(d,1H),8.11(m,1H),7.88(m,1H),7.62(m ,1H),6.74(m,1H),6.57(d,1H),4.93(s,2H),4.61,4.35(m,1H),4.36(m,1H),2.17(m,2H),2.00(m,2H),1.61(m,2H).

[0290] Example 145 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one Example 145 can also be prepared by following the procedure below. [ka]

[0291] Step 1 Following the synthesis method of Step 3 of Example 122, 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 145 was synthesized. MS m / z(ESI):457.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.10,8.61(d,1H),8.80(m,1H),8.70(s,1H),8.36(d,1H),8.15(m,1H),7.88(m,1H),7.56(m ,1H),6.73(m,1H),6.56(d,1H),4.96(s,2H),4.61,4.33(m,1H),4.35(m,1H),2.18(m,2H),2.00(m,2H),1.63(m,2H).

[0292] Example 146 5,5-Dimethyl-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Example 146 can also be prepared by following the procedure below. [ka]

[0293] Step 1 3-(Methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (390 mg, 2.00 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (420 mg, 2.10 mmol), and diisopropylethylamine (258 mg, 2.00 mmol) were dissolved in N-methylpyrrolidone (5 mL), and the reaction mixture was heated to 90 °C and stirred for 2 h. Ethyl acetate (25 mL) and water (10 mL) were added to the reaction mixture, and the organic phase was washed with saturated brine. The organic phase was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give tert-butyl ((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate 146a (410 mg) in a 59.07% yield. MS m / z (ESI): 348.2 [M + H] + .

[0294] Step 2 146a (410 mg, 1.18 mmol) was dissolved in methanol (3 mL), and the reaction mixture was added with 4 M hydrochloric acid in 1,4-dioxane (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in a small amount of methanol. Ammonia water was added to adjust the pH to alkaline, and the mixture was concentrated again. The residue was separated by silica gel column chromatography (elution system A) to give (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 146b (280 mg) in a yield of 95.95%. MS m / z(ESI):248.2[M+H] + .

[0295] Step 3 Under nitrogen gas protection, 146b (43 mg, 0.17 mmol), 93a (63 mg, 0.24 mmol), and diisopropylethylamine (56 mg, 0.43 mmol) were dissolved in dimethyl sulfoxide (1.5 mL), and the reaction mixture was heated to 130 °C and stirred for 48 h. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (formic acid system) to give 5-dimethyl-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 146 (28 mg) in 33.23% yield. MS m / z (ESI): 485.2 [M + H] + 1 H NMR(400MHz,DMSO-d6)δ9.17-8.60(m,1H),8.77-8.74(m,1H),8.71(d,1H),8.24(d,1H),7.87(d,1H),7.70-7.61(m,1H),7.35-7.2 7(m,1H),7.00-6.90(m,1H),6.58(d,1H),4.71-4.24(m,2H),2.27-2.11(m,2H),2.08-1.87(m,2H),1.73-1.52(m,2H),1.45(s,6H).

[0296] Example 147 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0297] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 147 was synthesized. MS m / z(ESI):459.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.66(dd,1H),8.34(d,1H),7.85(dd,1H),7.59(s,1H),7.27(dd,1H),6.86(td,1H),6.73(dd ,2H),6.55(d,1H),4.97(s,2H),4.29(q,1H),4.15(q,1H),2.60(s,3H),2.19-2.08(m,2H),1.99-1.83(m,2H),1.59-1.46(m,2H).

[0298] Example 148 6-methyl-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ka]

[0299] Following the synthesis method of Example 144, 6-methyl-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 148 was obtained. MS m / z (ESI): 471.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.80(s,1H),8.70(s,1H),8.35(d,1H),7.86(dd,1H),7.59(s,1H),6.76(d,1 H),6.56(d,1H),4.98(s,2H),4.61(d,1H),4.33(d,1H),2.60(s,3H),2.23-2.13(m,2H),1.99(d,2H),1.59(d,2H).

[0300] Example 149 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0301] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 149 was obtained. MS m / z(ESI):459.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.69-8.59(m,2H),8.37(d,1H),7.86(dd,1H),7.55(d,1H),7.27(dd,1H),6.86(td,1H),6.73(dd,2H) ),6.55(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.57(s,3H),2.21-2.09(m,2H),2.03-1.90(m,2H),1.59-1.44(m,2H).

[0302] Example 151 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one [ka]

[0303] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 151 was synthesized. MS m / z(ESI):513.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.66(t,1H),8.36(d,1H),8.16(s,1H),7.86(dd,1H),7.27(dd,1H),6.86(td,1H),6. 76(dd,2H),6.57(d,1H),5.13(s,2H),4.30(q,1H),4.15(q,1H),2.23-2.07(m,2H),2.03-1.84(m,2H),1.59-1.44(m,2H).

[0304] Example 152 6-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ka]

[0305] Following the synthesis method of Example 144, 6-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 152 was synthesized. MS m / z(ESI):525.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.10(d,1H),8.86(dd,1H),8.37(d,1H),8.16(s,1H),7.87(dd,1H),6.82 (d,1H),6.58(d,1H),5.14(s,2H),4.42-4.28(m,2H),2.28-2.09(m,2H),2.05-1.97(m,2H),1.75-1.49(m,2H).

[0306] Example 153 3-Fluoro-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0307] Following the synthesis method of Example 144, 3-fluoro-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 153 was synthesized. MS m / z (ESI): 475.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.76(s,1H),8.70(s,1H),8.34(d,1H),8.10(dd,1H),7.86(dd,1H),6.78-6.73(m,1H) ,6.56(d,1H),4.94(s,2H),4.36-4.32(m,2H),2.23-2.13(m,2H),2.02-1.91(m,2H),1.69-1.62(m,1H),1.57-1.51(m,1H).

[0308] Example 154 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide [ka]

[0309] Following the synthesis method of Example 121, 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide 154 was synthesized. MS m / z(ESI):493.1[M+H] + .

[0310] Example 155 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one [ka]

[0311] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 155 was obtained. MS m / z(ESI):513.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.41(d,1H),8.36(d,1H),8.14(d,1H),7.88(dd,1H),7.27(dd,1H),6.86(td,1H),6 .75(dd,2H),6.57(d,1H),5.04(s,2H),4.30(q,1H),4.16(q,1H),2.21-2.10(m,2H),2.03-1.84(m,2H),1.60-1.47(m,2H).

[0312] Example 156 6-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ka]

[0313] Following the synthesis method of Example 143, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 156 was obtained. MS m / z(ESI):509.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.80(s,1H),8.34(d,1H),7.85(d,2H),7.59(s,1H),7.15(dd,1H),7.03(dd,1H),6.72(d, 1H),6.55(d,1H),4.97(s,2H),4.31(q,1H),4.20(q,1H),2.60(s,3H),2.22-2.13(m,2H),2.01-1.86(m,2H),1.61-1.47(m,2H).

[0314] Example 157 7-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one [ka]

[0315] 7-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 157 was synthesized according to the synthesis method of Example 144. MS m / z(ESI):524.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.12-8.63(m,1H),8.70(d,1H),8.38(d,1H),8.05(d,1H),8.01(d,1H),7.84(dd,1H),7.78( t,1H),6.74(d,1H),6.55(d,1H),5.11(s,2H),4.61-4.33(m,2H),2.24-2.12(m,2H),1.96(d,2H),1.69-1.50(m,2H).

[0316] Example 158 4-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one [ka]

[0317] 4-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 158 was synthesized according to the synthesis method of Example 144. MS m / z(ESI):524.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.34(d,1H),8.18(s,1H),7.85(dd,1H),7.59(s,1H),7.54(s,1H),6.72(d,1H),6 .55(d,1H),4.97(s,2H),4.32(d,2H),2.60(s,3H),2.17-2.02(m,3H),1.90(dt,2H),1.52(dd,2H),0.98-0.87(m,4H).

[0318] Example 159 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0319] Following the synthesis method of Example 144, 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 159 was obtained. MS m / z (ESI): 497.2 [M + H] + .

[0320] Example 161 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one [ka]

[0321] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one 161 was synthesized according to the synthesis method of Example 129. MS m / z(ESI):512.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.30(d,1H),7.95(d,1H),7.90-7.77(m,3H),7.27(dd,1H),6.86(t,1H),6.75(d,1 H),6.68(d,1H),6.54(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.15(dd,2H),2.01-1.84(m,2H),1.61-1.44(m,2H).

[0322] Example 162 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one [ka]

[0323] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one 162 was synthesized. MS m / z(ESI):512.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.36(d,1H),8.03(dd,2H),7.89-7.70(m,2H),7.27(dd,1H),6.86(t,1H) ,6.72(dd,2H),6.54(d,1H),5.10(d,2H),4.22(d,2H),2.21-2.06(m,2H),2.00-1.81(m,2H),1.64-1.42(m,2H).

[0324] Example 163 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0325] Following the synthesis method of Example 143, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 163 was synthesized. MS m / z(ESI):513.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.75(s,1H),8.33(d,1H),8.09(dd,1H),7.87-7.83(m,2H),7.15(dd,1H),7.04(d,1H),6.72 (d,1H),6.56(d,1H),4.93(s,2H),4.35-4.29(m,1H),4.25-4.17(m,1H),2.20-2.13(m,2H),2.00-1.86(m,2H),1.62-1.48(m,2H).

[0326] Example 164 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka]

[0327] Step 1 To a solution of 2-bromo-6-tert-butylpyridine 164a (300 mg, 1.40 mmol) in tetrahydrofuran (5 mL) at -78 °C, diisopropylaminolithium (2 M, 1.05 mL) was added dropwise. The reaction was stirred at -78 °C for 1 hour. N,N-dimethylformamide (410 mg, 5.60 mmol) was added dropwise to the reaction mixture, and the mixture was slowly warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography to give 2-bromo-6-(tert-butyl)nicotinaldehyde 164b (56 mg) in 16.51% yield. MS m / z (ESI): 242.0 [M + H] + .

[0328] Step 2 Under carbon monoxide protection, 164b (53 mg, 0.22 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (16 mg, 0.02 mmol), and triethylamine (44 mg, 0.44 mmol) were dissolved in a mixture of N,N-dimethylformamide (1 mL) and methanol (2 mL), and the mixture was heated to 80 °C and stirred for 16 h. Saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography to give methyl 6-(tert-butyl)-3-formylpyridinecarboxylate 164c (13 mg) in a 26.84% yield. MS m / z(ESI):222.1[M+H] + .

[0329] Step 3 129e (23 mg, 0.07 mmol), 164c (13 mg, 0.06 mmol), and acetic acid (5 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (2 mL), and the reaction was heated to 60° C. and stirred for 1 h. After the reaction returned to room temperature, sodium triacetoxyborohydride (62 mg, 0.29 mmol) was added to the reaction, and the mixture was stirred for 15 h. The reaction mixture was added with saturated ammonium chloride solution and extracted with dichloromethane (20 mL × 2). The combined organic phases were dried, concentrated, and the residue was purified by reverse-phase HPLC to give 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 164 (15.8 mg), 53.72% yield. MS m / z (ESI): 501.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),8.34(d,1H),8.02(d,1H),7.89- 7.80(m,1H),7.68(d,1H),7.31-7.22(m,1H),6.90-6.82(m,1H),6.75(d,1H) ),6.68(d,1H),6.56(d,1H),4.86(s,2H),4.35-4.23(m,1H),4.22-4.08(m, 1H),2.22-2.07(m,2H),2.03-1.81(m,2H),1.63-1.42(m,2H),1.37(s,9H).

[0330] For the synthesis methods of the examples, reference may be made to the above examples.

[0331] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0332] Biological Test Evaluation The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0333] 1. Binding experiments 1. Purpose of the experiment: The binding activity of compounds to PCSK9 protein was detected using a conventional surface plasmon resonance (SPR) method. 2. Experimental results:

[0334] [Table 2] Note: E-04: x10 -4

[0335] 3. Experimental conclusion: The compounds of the Examples shown in the present invention had good binding activity to PCSK-9 protein, and the compounds had a slow dissociation rate from PCSK9 protein.

[0336] 2. Cell function experiments Test Example 1: Measurement of the effect of the compound of the present invention on the concentration of PCSK9 secreted from HepG2 cells 1. Experimental objective: To detect the inhibitory effect of compounds on PCSK9.

[0337] 2. Laboratory equipment and reagents: 2.1 Equipment: Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), water purifier (THERMO: Pacific T II + Micropure), plate washer (Thermo: WELLWASH VERSA), microwell plate shaker (Thermo: 88882006) 2.2 Reagents: CircuLex Human PCSK9 ELISA Kit (MBL: CY-8079), DMEM (Gibco: 31966-021) FBS (Sigma: S5394) Compound plate (Thermo: 1353506) Complete medium: DMEM+10%FBS+1XP / S, Experimental medium: DMEM + 10% FBS Cell line: HepG2 (ATCC:HB-8065)

[0338] 3. Experimental Method: 1) HepG2 cells were cultured in complete medium at 37°C and 5% CO2 until they reached 70% to 90% confluence.

[0339] 2) The cells were digested, resuspended in experimental medium, and seeded into a 96-well cell culture plate at 25,000 cells / well / 200 μL, and cultured at 37°C, 5% CO2 for 20 to 24 hours.

[0340] 3) The medium was removed from the cell culture plate, and 200 μl of experimental medium was added to each well, followed by washing once.

[0341] 4) Preparation of positive control compounds and test compounds: Positive control compounds and test compounds were diluted on a compound plate.

[0342] 5) The diluted compounds were added to the cell culture plate at 250 μL per well and incubated at 37° C., 5% CO 2 for 48 hours.

[0343] 6) 200 μL of cell culture medium was collected per well and frozen at -80°C for further use.

[0344] 7) Cell culture media samples were removed from -80°C, thawed, vortexed, centrifuged and ready for use.

[0345] 8) Standard curve layout: The corresponding volume of dilution buffer was added to each standard tube in sequence, and the standard was sequentially diluted by taking the corresponding volume from the original tube or the tube with the previous concentration in order of concentrations: 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, 0 ng / mL.

[0346] 9) Preparation of washing solution: Dilute 10x Wash buffer to 1x with Milli-Q and prepare for use.

[0347] 10) According to the standard curve wells and sample wells defined by the plate map, 100 μL of the corresponding standard and medium samples were added to each well in duplicate. After attaching a seal sheet, the wells were placed on a shaker, gently shaken to mix evenly, and incubated at room temperature for 1 hour.

[0348] 11) The plate was placed in a plate washer, and 350 μL of washing solution was added per well. This was repeated four times to wash the plate.

[0349] 12) 100 μL of HRP-conjugated detection antibody was added to each well, a seal sheet was attached, the wells were placed on a shaker, mixed thoroughly and uniformly, and incubated for 1 hour.

[0350] 13) The plate was placed in a plate washer, and 350 μL of washing solution was added per well. This was repeated four times to wash the plate.

[0351] 14) Add 100 μL of Substrate reagent to each well, shield from light, attach a seal sheet, place on a shaker, mix thoroughly and uniformly, and incubate for 10 to 20 minutes.

[0352] 15) 100 μL of stop solution (1N H2SO4) was added to each well and mixed evenly.

[0353] 16) The optical density (OD) value of each well was measured sequentially using a microplate reader at a wavelength of 450 nm. Detection was performed within 30 minutes after the reaction was completed.

[0354] 4. Experimental data processing method: The OD values ​​were read using a microplate reader, and the OD value of the standard group at 0 concentration was subtracted from the OD values ​​of the standard, control, and sample to obtain the actual value for each well. A standard curve was then plotted using Graphpad to calculate the sample concentration. If dilution was performed for sample detection, the actual concentration of the sample was calculated by multiplying by the corresponding dilution factor at the end of the calculation. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to various concentrations, a plot was made using Graphpad to calculate the IC 50 obtained.

[0355] 5. Experimental results: [Table 3-1] [Table 3-2]

[0356] 6. Experimental conclusion: The compounds of the Examples shown in the present invention showed good inhibitory effects in an experiment on the concentration of PCSK9 secreted from HepG2 cells.

[0357] Test Example 2: Measurement of the effect of the compound of the present invention on the LDLR level in HepG2 cells 1. Experimental Objective: The effect of the compounds on LDLR protein levels was detected.

[0358] 2. Laboratory equipment and reagents: 2.1 Equipment: Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), water purifier (THERMO: Pacific T II + Micropure), plate washer (Thermo: WELLWASH VERSA), microwell plate shaker (Thermo: 88882006) 2.2 Reagents: Human LDL R Quantikine ELISA Kit(R&D:DLDLR0) DMEM (Gibco: 31966-021) FBS (Sigma: S5394) PBS Cell cleavage solution (Thermo:78503) Protease inhibitor (Pierce: 78430) Compound plate (Thermo: 1353506) Complete medium: DMEM+10% FBS+1X P / S Experimental medium: DMEM + 10% FBS Cell line: HepG2 (ATCC:HB-8065)

[0359] 3. Experimental Method: 1) HepG2 cells were cultured in complete medium at 37°C and 5% CO2 until they reached 70% to 90% confluence.

[0360] 2) The cells were digested, resuspended in experimental medium, and seeded into a 96-well cell culture plate at 25,000 cells / well / 200 μL, and cultured at 37°C, 5% CO2 for 20 to 24 hours.

[0361] 3) The medium was removed from the cell culture plate, and 200 μl of experimental medium was added to each well, followed by washing once.

[0362] 4) Preparation of positive control compounds and test compounds: Positive control compounds and test compounds were diluted on a compound plate.

[0363] 5) The diluted compounds were added to the cell culture plate at 250 μL per well and incubated at 37° C., 5% CO 2 for 48 hours.

[0364] 6) The cell culture medium was removed, the cells were washed with PBS, and 50 pL of cell lysis solution and protein inhibitors were added.

[0365] 7) Centrifuge to remove cleavage material and store the sample for further use.

[0366] 8) Standard curve layout: The corresponding volume of dilution buffer was added to each standard tube in turn, and the standard was sequentially diluted by taking the corresponding volume from the original tube or the previous concentration tube.

[0367] 9) Preparation of washing solution: Dilute 10x Wash buffer to 1x with Milli-Q and prepare for use.

[0368] 10) According to the standard curve wells and sample wells defined by the plate map, 80 μL of the corresponding standard and sample were added to each well in duplicate. Wells to which no standard was added were used as background value wells. A seal sheet was attached, the plate was placed on a shaker, and the plate was gently shaken at room temperature to mix evenly, and then incubated for 2 hours.

[0369] 11) The plate was placed in a plate washer, and 350 μL of washing solution was added per well. This was repeated four times to wash the plate.

[0370] 12) 200 μL of human LDLR conjugate was added to each well, a sealing sheet was attached, the well was placed on a shaker, mixed thoroughly and uniformly, and incubated for 2 hours.

[0371] 13) The plate was placed in a plate washer, and 350 μL of washing solution was added per well. This was repeated four times to wash the plate.

[0372] 14) Add 200 μL of Substrate solution to each well, shield from light, attach a seal sheet, place on a shaker, mix thoroughly and uniformly, and incubate for 20 minutes.

[0373] 15) 50 μL of stop solution was added to each well and mixed evenly for 20 minutes.

[0374] 16) The optical density (OD) value of each well was measured sequentially using a microplate reader at a wavelength of 450 nm.

[0375] 4. Experimental data processing method: The OD values ​​were read using a microplate reader, and the OD value of the standard group at 0 concentration was subtracted from the OD values ​​of the standard, control, and sample to obtain the actual value for each well. A standard curve was then plotted using Graphpad to calculate the sample concentration. If sample dilutions were performed, the actual sample concentration was calculated by multiplying by the corresponding dilution factor. Concentration increase percentage % = (actual control concentration - actual sample concentration) / actual control concentration * 100. 5. Experimental results:

[0376] [Table 4]

[0377] 6. Experimental conclusion: In an experiment to measure the effect on LDLR concentration in HepG2 cells, the compounds of the Examples shown in the present invention showed an effect of increasing LDLR concentration.

[0378] 3. Pharmacokinetics Experiments Test Example 1: Pharmacokinetics measurement in mice 1. Experimental Objective: C57BL / 6J mice were used as test animals, and the pharmacokinetic behavior of the compound of the present invention in the mouse body (plasma) when administered orally or intravenously was examined.

[0379] 2. Test Scheme 2.1 Test Drugs: Compounds of the present invention, self-prepared.

[0380] 2.2 Test animals: C57 mice, male, Shanghai Bikai Laboratory Animal Co., Ltd., Animal Production Permit Number (SCXK(Shanghai) 2013-0006 N0.311620400001794).

[0381] 2.3 Drug Combinations: Oral drug formulation: 10% Solutol HS15 10 g of Solutol HS15 solid was weighed and dissolved in 90 mL of purified water, mixed, stirred uniformly, and sonicated to form a clear solution.

[0382] The compound of the present invention was weighed and dissolved in the solution, shaken well, and sonicated for 15 minutes to obtain a clear, colorless solution with a concentration of 0.5 mg / mL.

[0383] Intravenous drug formulation: 5% DMSO + 10% Solutol HS15 + 85% PBS The compound of the present invention was weighed out, and according to the proportion of the total volume to be administered, 5% DMSO was first added, vortexed, and sonicated for 2 minutes to completely dissolve, and then 10% Solutol HS15 was added, vortexed, and sonicated for 2 minutes to completely dissolve, and finally 85% PBS was added, vortexed, and sonicated for 5 minutes, and the solution was filtered through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[0384] 2.4 Administration: Three male C57 mice were administered PO after overnight fasting at a dose of 5 mg / kg and a dosing volume of 10 mL / kg.

[0385] Three male C57 mice were administered IV after an overnight fast, with a dose of 1 mg / kg and an administration volume of 5 mL / kg.

[0386] 2.5 Sampling: Before administration to mice and at 0.083(iv), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, 0.04 mL of blood was collected from the orbit of the mouse, placed in an EDTA-K2 test tube, and the plasma was centrifuged at 6000 rpm at 4°C for 6 minutes, stored at -80°C, and fed 4 hours after administration.

[0387] 2.6 Measurement results: The final measurement results were obtained by LCMS / MS method.

[0388] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0389] [Table 5]

[0390] 4. Experimental conclusion: Pharmacokinetic measurements in C57BL / 6J mice showed that the compounds of the present invention exhibited significant PK advantages.

[0391] 4. Medicinal efficacy experiments Test Example 1: In vivo pharmacological study of the compound of the present invention in a B6-hPCSK9 transgenic mouse hyperlipidemic animal model 1. Experimental Objective: The compounds were evaluated for in vivo efficacy in the B6-hPCSK9 transgenic mouse hyperlipidemic animal model.

[0392] 2. Laboratory equipment and reagents 2.1 Equipment Refrigerator (BCD-268TN, Haier) Biological safety cabinet (BSC-1300II A2, Shanghai Boken Industrial Co., Ltd. Medical Equipment Factory) Clean bench (CJ-2F, Suzhou Feng Experimental Animal Equipment Co., Ltd.) 5 mL pipette (Research Plus, Eppendorf) 1 mL pipette (Research Plus, Eppendorf) Constant temperature water bath (HWS-12, Shanghai Yiheng Science) Centrifuge (Centrifuge 5720R, Eppendorf) Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai Kedao) Pure water equipment (Pacific TII, Thermo) Magnetic stirrer (08-2G, Hashiku) Fully automatic biochemical analyzer (Hitachi 7180 model, HITACHI)

[0393] 2.2 Reagents High fat feed (Western Diet, D12079B) Physiological saline (MA0083-D, meilunbio) Solutol HS 15 (102483882, Sigma)

[0394] 2.3 Test drugs: compounds of the present invention, self-prepared

[0395] 3 Experimental procedures and data processing 3.1 Animals B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, were purchased from Jiangsu Jishui Pharmaceutical Co., Ltd.

[0396] 3.2 Animal models After the animals reached the barrier system, they were acclimated for one week and then started on a high-fat diet. Body weight and food intake were recorded.

[0397] 3.3 Grouping and administration a. Groups were assigned using a random grouping method.

[0398] c. Based on the results of grouping, administration of the test drug was initiated (administration method: oral administration, administration volume: 10 mL / kg, administration frequency: once daily or single administration; administration cycle: 21 days, vehicle: 10% Solutol HS 15 / 90% Saline).

[0399] d. After the start of test drug administration, body weight and food intake were measured twice a week, and blood samples were taken once a week.

[0400] e. Data were processed using software such as Excel. Body weight change rate (BWC) (%) = (body weight at the end of treatment - body weight at the start of treatment) / body weight at the start of treatment × 100%; food intake (g / mice / day) = (previous feed amount + previous remaining feed amount - current remaining feed amount) / number of animals / number of feeding days. Biochemical inhibition rates were calculated by normalizing the data for each treatment group using the biochemical results of the vehicle group detected in the same lot as the baseline. TC and LDL-C percentages were calculated according to the formula: TC percentage change (%) = (post-treatment TC value - pre-treatment TC value) / pre-treatment TC value × 100%; LDL-C percentage change (%) = (post-treatment LDL-C value - pre-treatment LDL-C value) / pre-treatment LDL-C value × 100%. Plasma PCSK9 was detected by ELISA.

[0401] 4 Experimental results: [Table 6]

[0402] 5. Experimental conclusion: The compounds of the Examples shown in the present invention were able to effectively reduce LDL-C in a B6-hPCSK9 transgenic mouse hyperlipidemic animal model.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 Ring A is selected from a 5-membered monoheteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and is preferably C ３－６ a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, C ３－６ a cycloalkyl group, a phenyl group, a 3- to 8-membered heterocyclyl group, a 7- to 10-membered bicyclic heterocyclyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group; More preferably, it is a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group or a 6-membered fused 6-membered bicyclic heteroaryl group; Ring A is preferably a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group, and Ring A is preferably a 6-membered monoheteroaryl group. 【Chemistry 2】 When the formula is 【Chemistry 3】 and wherein ring A is a 6-membered monoheteroaryl group. 【Chemistry 4】 [0039] When ring B is selected from a 5-membered fused 5-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heteroaryl group, a 5-membered fused 6-membered bicyclic heterocyclyl group, a 6-membered fused 5-membered bicyclic heteroaryl group, or a 6-membered fused 6-membered bicyclic heteroaryl group, and when ring A is a 6-membered fused 5-membered bicyclic heteroaryl group, ring A is 【Chemistry 5】 Instead, L １ is selected from a bond, —C(O)—, or —C(O)NH—; R ａ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, alkyl group, alkenyl group, alkynyl group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ａ１ ~R Ａ３ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R ａ are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R ｂ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｂ１ , -(CH ２ ) ｎ OR Ｂ１ , -(CH ２ ) ｎ C(O)R Ｂ１ , -(CH ２ ) ｎ C(O)OR Ｂ１ , -(CH ２ ) ｎ S (O) ｍ R Ｂ１ , -(CH ２ ) ｎ NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)OR Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)(CH ２ ) ｎ１ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ C(O)NR Ｂ２ (CH ２ ) ｎ１ R Ｂ３ , -OC(R Ｂ１ R Ｂ２ ) ｎ (CH ２ ) ｎ１ R Ｂ３ or -(CH ２ ) ｎ NR Ｂ２ S (O) ｍ R Ｂ３ wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｂ１ ~R Ｂ３ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R ｂ are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; Preferably, Or, any two R ａ and R ｂ are linked to form a heterocyclyl or heteroaryl group, and the heterocyclyl and heteroaryl groups optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; R ｃ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｃ１ , -(CH ２ ) ｎ OR Ｃ１ , -(CH ２ ) ｎ C(O)R Ｃ１ , -(CH ２ ) ｎ C(O)OR Ｃ１ , -(CH ２ ) ｎ S (O) ｍ R Ｃ１ , -(CH ２ ) ｎ NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or -(CH ２ ) ｎ NR Ｃ２ S (O) ｍ R Ｃ３ wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｃ１ ~R Ｃ３ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R ｃ are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; R ｄ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｄ１ , -(CH ２ ) ｎ OR Ｄ１ , -(CH ２ ) ｎ C(O)R Ｄ１ , -(CH ２ ) ｎ C(O)OR Ｄ１ , -(CH ２ ) ｎ S (O) ｍ R Ｄ１ , -(CH ２ ) ｎ NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or -(CH ２ ) ｎ NR Ｄ２ S (O) ｍ R Ｄ３ wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｄ１ ~R Ｄ３ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, which amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R ｄ are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; Or, any two R ｃ and R ｄ are joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; n4 is 0, 1, 2, 3 or 4, and The compound is 【Chemistry 6】 A compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is not:

2. The compound is further represented by general formula (III-1): 【Chemistry 7】 where: M １ is selected from N or CH; M ２ is selected from N or CH; M ３ is selected from N or CH, and M ４ is selected from N or CH, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. Ring A is a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazole group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, a pyridazinyl group, 【Chemistry 8】 is selected from Even more preferably, ring A is a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazole group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, a pyridazinyl group, 【Chemistry 9】 is selected from Preferably, it is a pyridyl group, a pyrazinyl group, a 1,2,4-triazinyl group, a 1,3,5-triazinyl group, or a pyridazinyl group; Or, Ring A is selected from an 8- to 12-membered bicyclic heteroaryl group, an 8- to 12-membered heteroaryl-fused aryl group, an 8- to 14-membered heteroaryl-fused cycloalkyl group or an 8- to 14-membered heteroaryl-fused heterocyclyl group, preferably 【Chemistry 10】 is selected from More preferably, 【Chemistry 11】 is selected from More preferably, 【Chemistry 12】 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

4. Further, the general formula (IE) 【Chemistry 13】 4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

5. Furthermore, it is as shown in general formula (I-1′): 【Chemistry 14】 where: Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; M ５ is N or CR ５ is selected from R ５ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, and the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R ａ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ａ１ ~R Ａ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ａ are bonded to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; R ｂ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ｂ１ , -(CH ２ ) ｎ OR Ｂ１ , -(CH ２ ) ｎ C(O)R Ｂ１ , -(CH ２ ) ｎ C(O)OR Ｂ１ , -(CH ２ ) ｎ S (O) ｍ R Ｂ１ , -(CH ２ ) ｎ NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)OR Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)(CH ２ ) ｎ１ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ C(O)NR Ｂ２ (CH ２ ) ｎ１ R Ｂ３ , -OC(R Ｂ１ R Ｂ２ ) ｎ (CH ２ ) ｎ１ R Ｂ３ or -(CH ２ ) ｎ NR Ｂ２ S (O) ｍ R Ｂ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｂ１ ~R Ｂ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ｂ are bonded to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two R ａ and R ｂ are linked to form a 5- to 12-membered heterocyclyl group or a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heterocyclyl group or the 5- to 12-membered heteroaryl group optionally contains deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, R ５ and R ｂ are linked to form a 5- to 12-membered heterocyclyl group or a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heterocyclyl group or the 5- to 12-membered heteroaryl group optionally contains deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; R ｃ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ｃ１ , -(CH ２ ) ｎ OR Ｃ１ , -(CH ２ ) ｎ C(O)R Ｃ１ , -(CH ２ ) ｎ C(O)OR Ｃ１ , -(CH ２ ) ｎ S (O) ｍ R Ｃ１ , -(CH ２ ) ｎ NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or -(CH ２ ) ｎ NR Ｃ２ S (O) ｍ R Ｃ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｃ１ ~R Ｃ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ｃ are bonded to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; R ｄ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ an aryl group, a 5- to 14-membered heteroaryl group, —(CH ２ ) ｎ R Ｄ１ , -(CH ２ ) ｎ OR Ｄ１ , -(CH ２ ) ｎ C(O)R Ｄ１ , -(CH ２ ) ｎ C(O)OR Ｄ１ , -(CH ２ ) ｎ S (O) ｍ R Ｄ１ , -(CH ２ ) ｎ NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or -(CH ２ ) ｎ NR Ｄ２ S (O) ｍ R Ｄ３ wherein the amino group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, cyano group-substituted C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１２ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｄ１ ~R Ｄ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ｄ are bonded to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; Or, any two R ｃ and R ｄ are bonded to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally contain deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; 4. The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein n1 is 0, 1, 2, 3 or 4.

6. Furthermore, general formula (I-1), (I-2), (I-3), (I-4) or (I-5) 【Chemistry 15】 4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

7. Ring B is pyridine, pyrimidine, benzene, 【Chemistry 16】 is selected from Even more preferably, Ring B is pyridine, pyrimidine, benzene, 【Chemistry 17】 is selected from More preferably, ring B is pyridine, pyrimidine, benzene, 【Chemistry 18】 is selected from More preferably, ring B is pyridine, pyrimidine, benzene, 【Chemistry 19】 is selected from More preferably, ring B is pyridine, pyrimidine, benzene, 【Chemistry 20】 The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1, 4 to 6, characterized in that it is selected from the group consisting of:

8. Furthermore, the general formula (V) 【Chemical 21】 6. The compound according to any one of claims 1 to 3 or 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

9. R ａ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ａ１ ~R Ａ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; Preferably, R ａ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S (O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S (O) ｍ R Ａ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R Ａ１ ~R Ａ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R ｂ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ｂ１ , -(CH ２ ) ｎ OR Ｂ１ , -(CH ２ ) ｎ C(O)R Ｂ１ , -(CH ２ ) ｎ C(O)OR Ｂ１ , -(CH ２ ) ｎ S (O) ｍ R Ｂ１ , -(CH ２ ) ｎ NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)OR Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)(CH ２ ) ｎ１ R Ｂ３ , -(CH ２ ) ｎ NR Ｂ２ C(O)NR Ｂ２ R Ｂ３ , -(CH ２ ) ｎ C(O)NR Ｂ２ (CH ２ ) ｎ１ R Ｂ３ , -OC(R Ｂ１ R Ｂ２ ) ｎ (CH ２ ) ｎ１ R Ｂ３ or -(CH ２ ) ｎ NR Ｂ２ S (O) ｍ R Ｂ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R Ｂ１ ~R Ｂ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R ｃ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ｃ１ , -(CH ２ ) ｎ OR Ｃ１ , -(CH ２ ) ｎ C(O)R Ｃ１ , -(CH ２ ) ｎ C(O)OR Ｃ１ , -(CH ２ ) ｎ S (O) ｍ R Ｃ１ , -(CH ２ ) ｎ NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ , -(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ , -(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or -(CH ２ ) ｎ NR Ｃ２ S (O) ｍ R Ｃ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R Ｃ１ ~R Ｃ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R ｄ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ｄ１ , -(CH ２ ) ｎ OR Ｄ１ , -(CH ２ ) ｎ C(O)R Ｄ１ , -(CH ２ ) ｎ C(O)OR Ｄ１ , -(CH ２ ) ｎ S (O) ｍ R Ｄ１ , -(CH ２ ) ｎ NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or -(CH ２ ) ｎ NR Ｄ２ S (O) ｍ R Ｄ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; R Ｄ１ ~R Ｄ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; Preferably, R ｄ represents hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, —(CH ２ ) ｎ R Ｄ１ , -(CH ２ ) ｎ OR Ｄ１ , -(CH ２ ) ｎ C(O)R Ｄ１ , -(CH ２ ) ｎ C(O)OR Ｄ１ , -(CH ２ ) ｎ S (O) ｍ R Ｄ１ , -(CH ２ ) ｎ NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ , -(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ , -(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or -(CH ２ ) ｎ NR Ｄ２ S (O) ｍ R Ｄ３ wherein the amino group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, cyano group-substituted C １－３ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be further substituted, and may optionally contain deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 12-membered heteroaryl groups; R Ｄ１ ~R Ｄ３ are each independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 12-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The aryl and 5- to 12-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 8, which may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 12-membered heteroaryl group.

10. The following compound, its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

11. A compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 28】 X is an amino group, a halogen, a boronic acid, or a boronic ester; A compound represented by general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each of the other groups is as defined in claim 2.

12. A method for producing a compound represented by general formula (III-1) according to claim 2, comprising the following steps: 【Chemical 29】 where: X １ is an amino group, a methylthio group, a halogen, a boronic acid or a boronic ester, Reacting the compound of general formula (VI) with the compound of general formula (VI-1) to obtain the compound of general formula (III-1), 12. The method of claim 11, wherein each of the other groups is as defined in claim 11.

13. A compound represented by general formula (VI-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 30】 R １１ is selected from hydrogen, an amino protecting group, a 5- to 6-membered heteroaryl group, and a 5- to 6-membered heterocyclyl group, wherein the 5- to 6-membered heteroaryl group and the 5- to 6-membered heterocyclyl group are optionally protected by deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ further substituted with one or more substituents selected from aryl and 5- to 14-membered heteroaryl groups; the amino protecting group is selected from an allyloxycarbonyl group, a trifluoroacetyl group, a tert-butylsulfinyl 2,4-dimethoxybenzyl group, a nitrobenzenesulfonyl group, a trityl group, a fluorenylmethoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl group, a p-toluenesulfonyl group, a p-methoxybenzyl group, a formate ester, an acetyl group, a benzyloxycarbonyl group, a phthaloyl group, a tert-butoxycarbonyl group, a benzyl group, or a p-methoxyphenyl group; The general formula (VI-2) is more preferably as shown in the general formula (VI-3): 【Chemical 31】 where: X ２ is an amino group, a halogen atom, a boronic acid, or a boronic acid ester, and the other groups are as defined in claim 8, a compound represented by general formula (VI-2), its stereoisomer, or a pharmaceutically acceptable salt thereof.

14. A method for producing a compound represented by general formula (V) according to claim 8, comprising the steps of: Method 1: 【Chemical 32】 where: X ３ is a halogen, a boronic acid or a boronic ester; The compound of general formula (VI-2) is reacted with the compound of general formula (VI-4) to obtain the compound of general formula (V), Each of the other groups is as defined in claim 13, Method 2: 【Chemical 33】 where: X ４ is a formaldehyde group, a hydroxymethyl group, or a halomethyl group, R １２ is C １－６ Alkyl group, C １－６ Deuterated alkyl group or C １－６ haloalkyl groups, The compound of general formula (VI-3) is reacted with the compound of general formula (VI-5) to obtain the compound of general formula (V), 14. The method of claim 13, wherein each of the other groups is as defined in claim 13.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 10 and its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. The use of the general formula (I) according to any one of claims 1 to 10 and its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 15, in the manufacture of a PCSK9 inhibitor drug.

17. 16. Use of the general formula (I) according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 15 in the manufacture of an LDL-lowering drug.

18. 13. The use of the general formula (I) according to any one of claims 1 to 10 and its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a medicament for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or diseases related thereto or symptoms thereof, preferably in the manufacture of a medicament for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipoprotein metabolism disorder, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

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