INHIBITOR WHICH IS A NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE, AND A METHOD FOR ITS PRODUCTION, AS WELL AS ITS USE

Abstract

The present invention relates to a nitrogen-containing heterocyclic derivative inhibitor, and a preparation method therefor and the use thereof. In particular, the present invention relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an inhibitor in the treatment of diseases such as cardiovascular diseases and cerebrovascular diseases, wherein the definition of each substituent in general formula (I) is the same as that defined in the description.

Description

A class of nitrogen-containing heterocyclic derivative inhibitors, preparation method and application thereof

[0001] This application claims priority to:

[0002] CN202310818758.5, application date July 4, 2023;

[0003] CN202311011109.0, application date August 10, 2023;

[0004] CN202311227801.7, application date September 21, 2023;

[0005] CN202311552677.1, filed on November 17, 2023;

[0006] CN202410052828.5, application date January 12, 2024;

[0007] CN202410173281.4, application date February 6, 2024;

[0008] CN202410407937.4, application date April 3, 2024;

[0009] CN202410426055.2, application date April 9, 2024. Technical Field

[0010] The present invention belongs to the field of drug synthesis, and in particular relates to a class of nitrogen-containing heterocyclic derivative inhibitors and a preparation method and application thereof. Background Art

[0011] Cardiovascular disease (CVD) is the leading cause of death worldwide. High levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C in the arterial lining can lead to atherosclerosis and potentially trigger an inflammatory response, leading to cardiovascular events such as heart attack and stroke. While statins can lower serum LDL-C and are currently the mainstay of lipid-lowering therapy in clinical practice, patients who are intolerant to statins or who fail to achieve treatment goals at tolerated doses remain at risk, such as those with familial hypercholesterolemia. The discovery of PCSK9 inhibitors offers a more aggressive approach for patients with homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when combined with a statin, can reduce LDL-C by 15%-20%, while the combination of a PCSK9 inhibitor and a statin can significantly reduce LDL-C by 54%-74%. PCSK9 inhibitors can also overcome intolerable side effects of statins, such as muscle pain.

[0012] PCSK9 (Proprotein convertase subtilisin kexin type 9) 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), and it has been clinically validated as a therapeutic target for hyperlipidemia. PCSK9 is synthesized as a precursor enzyme, which undergoes autocatalytic cleavage within the cell. The propeptide binds to mature PCSK9 and is secreted extracellularly. This propeptide binding blocks PCSK9's catalytic activity.

[0013] PCSK9 is a major regulator of low-density lipoprotein receptor (LDLR) levels on the hepatocyte surface and can inhibit the LDLR recycling pathway. LDLR function is crucial for maintaining cholesterol homeostasis, responsible for the uptake and degradation of low-density lipoprotein (LDL). Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100. The LDL / LDLR complex is internalized through receptor-mediated endocytosis. The low intracellular pH environment triggers LDL release from the LDLR, which then recycles back to the cell membrane. Intracellular free LDL is then delivered to the lysosome for degradation. Secreted PCSK9 interferes with LDLR recycling by binding to the LDLR on the hepatocyte surface. After the PCSK9 / LDLR complex migrates through clathrin-coated pits into the acidic endosomal compartment, conformational changes in the LDLR lead to the formation of additional binding sites for PCSK9. Consequently, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR recycling and thereby upregulating LDL-C levels.

[0014] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein (LDL) cholesterol metabolism that affects 1 in 250 people and is characterized by significantly elevated LDL-C levels. Heterozygous FH patients have a three- to four-fold increased risk of developing coronary artery disease (CAD), and CAD often develops an average of 10 years earlier. Statins lower LDL cholesterol in heterozygous FH patients. In a study by Besselin et al., high-intensity statin therapy was shown to reduce the risk of CHD and mortality by 44%. However, in many cases, LDL-C reduction is considered insufficient. The counteracting mechanism of statins is upregulation of sterol regulatory element binding protein 2 (SREBP-2), which activates the LDL receptor and PCSK9. This increases PCSK9 expression and secretion, which binds to the LDLR and leads to elevated LDL-C levels. Therefore, while statins lower LDL cholesterol by inhibiting HMG-CoA, they counteract the effects of SREPB. 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 approaches such as PCSK9 inhibitors are needed.

[0015] Alirocumab and evolocumab, monoclonal antibody-based macromolecular inhibitors of PCSK9, selectively bind to extracellular PCSK9 and prevent its interaction with the LDLR. They have been approved by the FDA for lowering LDL-C levels with a favorable safety profile. Studies have shown that in heterozygous FH patients who have not achieved their LDL-C target on statin therapy alone, alirocumab, administered by injection every two weeks, provides the greatest reduction in cardiovascular risk. Alirocumab has also been shown to modestly increase "good" cholesterol (HDL-C). Inclisiran, a PCSK9 siRNA drug currently on the market, is reportedly designed to reduce PCSK9 protein expression for long-term lipid-lowering effects and has a favorable safety profile. However, both drugs require injection, are expensive to produce, and are therefore expensive. To date, there are no marketed small-molecule PCSK9 inhibitors, leading to a high demand for oral small-molecule PCSK9 inhibitors.

[0016] Patents for small molecule PCSK9 inhibitors have been published, including WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ), and WO2022133529 (Nyrada). Currently, AZD-0780, the most advanced candidate, is in Phase I clinical trials, while the others are in preclinical development. Several peptides have also been reported, with the most advanced in Phase II clinical trials. The present invention seeks to develop orally available small molecule PCSK9 inhibitors.

[0017] Summary of the Invention

[0018] The 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 compound represented by general formula (I) has the following structure:

[0019] Wherein: Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0020] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0021] L1 is selected from a bond, -(CH2) n -、-(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CH2) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n O(CR aa R bb ) n1 -、-(CR aa R bb ) n3 S(CH2) n4 -、-(CH2) n S(CR aa R bb ) n3 -、-(CR aa R bb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-、-(CH2) n P(O) p R aa -、-(CH2) n S(O) m -、-(CH2)n C(O)NR aa R bb -、-(CH2) n NR cc C(O)R dd -、-(CH2) n S(O) m NR aa R bb - and -(CH2) n NR cc S(O) m R dd -;

[0022] R aa 、R bb、 R cc and R dd each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0023] Alternatively, any two adjacent or non-adjacent substituents are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted;

[0024] Preferably, L1 is selected from a bond, -C(O)- or -C(O)NH-;

[0025] R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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) nNR 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 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0026] R A1 ~R A3 each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0027] Preferably, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(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 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0028] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0029] Or, any two adjacent or non-adjacent R a Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0030] R b is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0031] R B1 ~R B3 each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0032] Preferably, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(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 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0033] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0034] Or, any two adjacent or non-adjacent R b Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0035] Preferably, or, any two R a and R bThe heterocyclic group and heteroaryl group are optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1- 6-halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0036] R c is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0037] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0038] Preferably, R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(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 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0039] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0040] Or, any two adjacent or non-adjacent R c Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0041] R d is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0042] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0043] Preferably, R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(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 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0044] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0045] Or, any two adjacent or non-adjacent R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0046] Or, any two R c and R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0047] x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; z is 0, 1, 2, or 3;

[0048] e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4;

[0049] n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4;

[0050] n3 is 0, 1, 2, 3 or 4; n4 is 0, 1, 2, 3 or 4.

[0051] In a preferred embodiment of the present invention, the compound is further represented by formula (IA):

[0052] Wherein: Ring A is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from 5-membered nitrogen-containing heteroaryl, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl;

[0053] Ring B is selected from C 3-8 Cycloalkyl, 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered and 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered and 5-membered bicyclic nitrogen-containing heterocyclic group or 6-membered and 6-membered bicyclic nitrogen-containing aryl group;

[0054] R c-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0055] R C1 ~R C3are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; preferably, R c-1 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0056] Or, R c-1 Preferably selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1- 3 haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0057] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0058] Preferably, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0059] More preferably, R c-1 Selected from -F;

[0060] R c-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 RC3 、-(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1- 3 haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0061] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0062] Preferably, R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0063] R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3Alkoxy, C 1-3 Deuterated alkoxy, C 1- 3 haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0064] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0065] Preferably, R c-3Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0066] More preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0067] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4;

[0068] Other groups are as defined above.

[0069] In a preferred embodiment of the present invention, the compound is further represented by the general formula (IA-1):

[0070] The groups are as defined above.

[0071] In a more preferred embodiment of the present invention, the ring A of the present invention is selected from a 5-membered monoheteroaryl, a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered monoheteroaryl, a 6-membered and 5-membered bicyclic heteroaryl or a 6-membered and 6-membered bicyclic heteroaryl;

[0072] Further selected from

[0073] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-2'):

[0074] L1 is selected from a bond, -C(O)-, -C(O)NH-, -C(O)NCH3- or -C(O)N(CH3)2; M5 is selected from N or CR5;

[0075] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-12 Aryl, 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are substituted by one or more substituents; other groups are as defined above.

[0076] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1-a):

[0077] Where: R a-1 ~R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) nOR 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 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0078] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0079] Other groups are defined as above;

[0080] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n1 is 0, 1, 2, 3 or 4.

[0081] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1-a'):

[0082] The groups are as defined above.

[0083] In a more preferred embodiment of the present invention, the ring B of the present invention is selected from C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered and 5-membered bicyclic heteroaryl, or 6-membered and 6-membered bicyclic heteroaryl;

[0084] More preferably, ring B is selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group;

[0085] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0086] Further preferably, ring B is selected from pyridine, pyrimidine, pyridone or pyrimidone;

[0087] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0088] In a further preferred embodiment of the present invention, the R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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) n1R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0089] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0090] Preferably, R aSelected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0091] More preferably, R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0092] More preferably, R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3-CHF2, -CF3, -CH2-OH, -CH2- CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2,

[0093] In a further preferred embodiment of the present invention, the R a-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0094] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0095] Preferably, R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0096] More preferably, R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0097] In a further preferred embodiment of the present invention, the R a-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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, the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0098] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0099] Preferably, R a-2Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2- OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0100] More preferably, R a-2 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0101] In a further preferred embodiment of the present invention, the R a-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0102] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0103] Preferably, R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0104] More preferably, R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0105] In a further preferred embodiment of the present invention, the R a-4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0106] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0107] Preferably, R a-4 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2- OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0108] More preferably, R a-4Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0109] In a further preferred embodiment of the present invention, the R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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)NRB2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0110] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0111] Preferably, R b Selected from -H or -F.

[0112] In a further preferred embodiment of the present invention, any two R b Linking with adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-12 membered heteroaryl.

[0113] In a further preferred embodiment of the present invention, the R a and R b The 5-12 membered heterocyclic group or 5-12 membered heteroaryl group is linked to form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0114] In a further preferred embodiment of the present invention, the R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 NRC2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0115] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0116] Preferably, R c Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0117] More preferably, R c Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0118] In a further preferred embodiment of the present invention, the R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(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 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0119] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0120] Preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CD3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0121] More preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0122] More preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH,

[0123] In a further preferred embodiment of the present invention, the compound Selected from

[0124] In a further preferred embodiment of the present invention, the compound Selected from where R c-1 、R c-2 and R c-3 The definition is the same as R c Preferably, R c-1 、R c-2 and R c-3 The definition of R is as above c-1 、R c-2 and R c-3 Definition of .

[0125] The present invention further provides a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0126] Wherein: X2 is amino, nitro, halogen, boronic acid or boric acid ester; other groups are as described above;

[0127] Preferably, the compound represented by general formula (IV) is further represented by (IV-A), (IV-B) or (IV-C):

[0128] In a further preferred embodiment of the present invention, the compound of formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof are characterized in that they are selected from the following compounds:

[0129] The present invention further provides a method for preparing the compound represented by general formula (IA), comprising the following steps:

[0130] Wherein: X3 is hydroxyl, amino, halogen, boric acid or boric acid ester;

[0131] The compound of formula (IV) reacts with the compound of formula (IV-1) to obtain the compound of formula (IA);

[0132] The other groups are as described above;

[0133] Preferably, the compound represented by the general formula (IA) is further represented by (IA-1), (I-1-a) or (I-1-a'):

[0134] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0135] The present invention further relates to the use of any compound of the general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of PCSK9 inhibitor drugs.

[0136] The present invention further relates to the use of any compound of the general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of LDL-lowering drugs; preferably, the LDL is LDL-C.

[0137] The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms; preferably, in the preparation of a drug for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0138] The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a method for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms, preferably in preparing a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0139] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0140] Furthermore, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0141] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with PCSK9.

[0142] The present invention also relates to a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0143] Detailed Description of the Invention

[0144] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0145] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight 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, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 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 point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0146] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0147] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0148] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0149] wait;

[0150] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0151] wait.

[0152] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0153] wait.

[0154] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0155] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0156] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining 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; further preferably, it contains 1 to 3 nitrogen atoms, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups; or, preferably, it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, further preferably, it contains 1 to 3 nitrogen and / or oxygen atoms, a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterocyclic group.

[0157] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0158] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include: wait.

[0159] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered and 5-membered or 5-membered and 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include: wait.

[0160] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include: wait.

[0161] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

[0162] The heterocyclyl group may be optionally substituted or unsubstituted. When 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, oxo, carboxyl or carboxylate.

[0163] The term "aryl" 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. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0164] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include: wait.

[0165] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0166] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 12-membered, more preferably a 5- or 6-membered monocyclic heteroaryl group or an 8-12-membered bicyclic heteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, pyridazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0167] The bicyclic heteroaryl is preferably a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered and 5-membered bicyclic heteroaryl, or a 6-membered and 6-membered bicyclic heteroaryl. Non-limiting examples include:

[0168] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

[0169] The heteroaryl group may be optionally substituted or unsubstituted, and when 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, oxo or carboxylate.

[0170] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0171] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0172] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0173] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0174] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0175] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0176] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0177] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0178] Different expressions 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 express the same meaning, that is, X can be any one or more of A, B, and C.

[0179] The enol structure and the lactam structure in the compound of the present invention are tautomers, and those skilled in the art should know that they are the same molecule. For the same molecule.

[0180] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0181] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0182] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0183] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0184] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0185] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0186] Example

[0187] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O). The internal standard (if any) is tetramethylsilane (TMS).

[0188] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0189] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0190] The compound of the present invention has significant advantages in drugability such as solubility, permeability, and safety.

[0191] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0192] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0193] The eluent systems for silica gel column chromatography and the developing solvent systems for thin-layer chromatography used for the intermediates and purified compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0194] Unless otherwise specified, in the examples of the present invention, the ratios of the mobile phases in the HPLC chiral separation conditions and HPLC chiral analysis conditions are volume ratios.

[0195] Intermediate 1

[0196] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0197] Referring to the preparation method of patent WO2020150473A2, intermediate 1 was synthesized.

[0198] MS m / z(ESI):245.1[M+H] + .

[0199] Intermediate 1 can also be obtained by the following method:

[0200] Step 1: Dissolve 2-chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) in dimethyl sulfoxide (10 mL). Heat the reaction mixture to 100°C and stir for 5 hours. Cool the reaction mixture to room temperature, pour it into water (50 mL), and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to obtain 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] + .

[0201] Step 2: 1B (2.1 g, 6.1 mmol) was dissolved in methanol (10 mL), and a solution of hydrochloric acid in dioxane (4 M, 20 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and ammonia methanol solution (7 M, 10 mL) was added to adjust the pH to a weak alkaline state. After further concentration, the residue was purified by silica gel chromatography (elution system A) to obtain (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g), yield: 87.3%. MS m / z (ESI): 245.1 [M+H] + .

[0202] Intermediate 2

[0203] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0204] Step 1: Dissolve 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) in 1,4-dioxane (75 mL). Heat the reaction to 100°C and stir for 16 hours. Cool the reaction mixture to room temperature, pour it into 100 mL of water, and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to afford 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (3.1 g) in a 72.7% yield. MS m / z (ESI): 191.1 [M+H] + .

[0205] Step 2: Dissolve tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 130°C and stir for 16 hours. Cool the reaction mixture to room temperature, pour it into water (100 mL), and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to provide tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g) in a yield of 78.4%. MS m / z (ESI): 371.2 [M+H] + .

[0206] Step 3: Dissolve tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g, 7.83 mmol) in 4 M hydrochloric acid in dioxane (30 mL) and stir at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse phase chromatography (eluent system C) to afford 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one intermediate 2 (1.5 g) in a 70.9% yield. MS m / z (ESI): 271.2 [M+H] + .

[0207] Reference Example 1

[0208] 6'-((3-(((1S,3S)-7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0209] Step 1: Dissolve 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine Reference Example 1a (100 mg, 0.657 mmol) in acetonitrile under ice and stir. Add sodium nitrite (91 mg, 1.31 mmol) to the reaction mixture and continue stirring for 1 minute. Add hydrochloric acid (4 M, 0.41 mL) dropwise to the reaction mixture. Warm the reaction mixture to room temperature and continue stirring. Completion of the reaction is monitored by thin-layer chromatography. Add saturated sodium bicarbonate solution dropwise to pH 7. The reaction mixture is extracted with dichloromethane (10 mL x 3). The organic phase is dried and concentrated. The residue is separated by silica gel column chromatography (eluent system A) to afford 2-chloro-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine Reference Example 1b (65 mg) in a yield of 77.5%. MS m / z (ESI): 172.1 [M+H]. + .

[0210] Step 2: Under nitrogen, Reference Example 1b (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 solution was heated to 130°C and microwaved for 2 hours. The reaction solution was heated to 130°C under nitrogen for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC (basic 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'-bipyridyl]-2-one Reference Example 1 (6.6 mg) in a 4.08% yield. MS m / z (ESI): 406.2 [M+H] + .

[0211] 1H 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).

[0212] Reference Example 2

[0213] 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

[0214] Step 1: Under nitrogen, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine Reference Example 2a (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-bis(diphenylphosphino-9,9-dimethylxanthene) (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was 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 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 Reference Example 2b (240 mg) in a 30.9% yield. MS m / z (ESI): 336.0 [M+H] + .

[0215] Step 2: Dissolve Reference Example 2b (202 mg, 0.60 mmol) in methanol (2 mL) at room temperature with stirring. Add a 4 M solution of hydrochloric acid in 1,4-dioxane (5 mL). Stir the reaction mixture at room temperature for 1 hour. Concentrate the reaction mixture, and purify the residue by preparative HPLC (ammonia system) to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine Reference Example 2c (140 mg) in a 98.6% yield. MS m / z (ESI): 236.2 [M+H] + .

[0216] Step 3: Reference Example 2c (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). The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N3-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine Reference Example 2d (190 mg) in an 83.4% yield. MS m / z (ESI): 358.1 [M+H] + .

[0217] Step 4: Under a hydrogen atmosphere, Reference Example 2d (190 mg, 0.53 mmol) and palladium on carbon (28 mg, 0.026 mmol, 10% content) were dissolved in methanol (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to afford N2-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine Reference Example 2e (170 mg) in a 97.7% yield. MS m / z (ESI): 328.1 [M+H] + .

[0218] Step 5: Reference Example 2e (80 mg, 0.24 mmol), methyl 3-(bromomethyl)picolinate (62 mg, 0.27 mmol), and potassium carbonate (101.2 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature 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 Reference Example 2 (24.3 mg) in a yield of 22.4%. MS m / z (ESI): 445.2 [M+H] + .

[0219] 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).

[0220] Reference Example 3

[0221] 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

[0222] Referring to the synthesis method of Reference Example 2, 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 Reference Example 3 was synthesized. MS m / z (ESI): 495.2 [M+H] + .

[0223] 1H 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(d,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).

[0224] Reference Example 3 can also be prepared by referring to the following method:

[0225] Step 1: Dissolve 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and ethyl N-(thiomethylene)carbamate (4.85 g, 37.01 mmol) in 1,2-dichloroethane (50 mL) at room temperature and stir for 16 hours. The reaction mixture was concentrated to obtain ethyl N-[[4-(trifluoromethyl)-2-pyridinyl]carbamoylthioyl]carbamate Reference Example 3a (9.05 g), which was used directly in the next step without purification. MS m / z (ESI): 294.1 [M+H] + .

[0226] Step 2: Dissolve Reference Example 3a (9 g, 30.69 mmol), hydroxylamine hydrochloride (10.66 g, 153.44 mmol), and N,N-diisopropylethylamine (11.90 g, 92.07 mmol) in methanol (100 mL) and stir at room temperature for 20 minutes. Then, heat to 65°C and stir for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Reference Example 3b (5.0 g) in an 80.60% yield. MS m / z (ESI): 203.1 [M+H] + .

[0227] Step 3: Dissolve Reference Example 3b (5 g, 24.74 mmol) and copper bromide (5.52 g, 24.74 mmol) in acetonitrile (50 mL), and add tert-butyl nitrite (12.75 g, 123.68 mmol). The reaction was stirred at room temperature for 0.5 hours, then heated to 70°C and stirred for 2 hours. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (150 mL) and filtered. The organic phase was washed with water (100 mL) and concentrated. The residue was purified by silica gel column chromatography (elution system A) to provide 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine Reference Example 3c (5 g) in a yield of 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0228] Step 4: Under nitrogen, Reference Example 3c (4.5 g, 16.92 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (3.39 g, 16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylideneacetone)dipalladium (2.32 g, 2.54 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (2.94 g, 5.07 mmol) were dissolved in 1'4-dioxane (120 mL). The reaction mixture was heated to 130°C and stirred for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give tert-butyl N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]carbamate Reference Example 3d (3.7 g) in a yield of 56.76%. MS m / z (ESI): 386.2 [M+H] + .

[0229] Step 5: Dissolve Reference Example 3d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) in methanol (10 mL) and stir at room temperature for one hour. The reaction mixture was concentrated, the residue diluted with methanol, and the pH adjusted to 8-10 with saturated sodium bicarbonate solution. After concentration, the residue was purified by silica gel column chromatography (elution system A) to provide (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine Reference Example 3e (2.74 g) in a 100% yield. MS m / z (ESI): 286.2 [M+H] + .

[0230] Step 6: Reference Example 3e (2.74 g, 9.61 mmol), 2-fluoro-5-nitro-pyridine (1.50 g, 10.57 mmol), and cesium carbonate (7.82 g, 24.01 mmol) were dissolved in N,N-dimethylformamide (40 mL), heated to 80°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 B) to obtain (1S,3S)-N1-(5-nitropyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine Reference Example 3f (3.8 g) in a yield of 97.12%. MS m / z (ESI): 408.1 [M+H] + .

[0231] Step 7: Under a hydrogen atmosphere, Reference Example 3f (3.8 g, 9.33 mmol) and palladium on carbon (993 mg, 0.93 mmol, purity: 10%) were dissolved in methanol (60 mL) and stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine Reference Example 3g (3.2 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 378.1 [M+H] +

[0232] Step 8: Dissolve Reference Example 3g (2.0g, 5.30mmol), methyl 3-(bromomethyl)pyridine-2-carboxylate (1.30g, 4.24mmol) and N,N-diisopropylethylamine (2.05g, 15.90mmol) in a mixed solvent of tert-butanol (20mL) and N,N-dimethylformamide (4mL). Stir at room temperature for 1 hour, then raise the temperature to 40°C and stir for 16 hours, and then raise the temperature to 80°C and stir for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 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 Reference Example 3 (1.2 g) in a yield of 45.79%. MS m / z (ESI): 495.2 [M+H] +

[0233] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.75(dd,1H),8.35(d,1H),8.10(d,1H),7.92–7.82(m,2H),7.61(dd,1H),7.15(dd,1H),7 .02(d,1H),6.69(d,1H),6.56(d,1H),4.92(s,2H),4.32-4.13(m,2H),2.23–2.10(m,2H),2.04–1.85(m,2H),1.67–1.43(m,2H).

[0234] Reference Example 4

[0235] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

[0236] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine Reference Example 4a (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 hours. The reaction mixture was returned to room temperature, and saturated sodium chloride solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one Reference Example 4b (1.4 g, light yellow solid) in a yield of 57.87%. MS m / z (ESI): 246.1 [M+H] + .

[0237] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one Reference Example 4b (77 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL) and stirred at 130°C for 48 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was separated by reverse phase HPLC (ammonium bicarbonate system) to obtain 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one Reference Example 4 (41 mg, white solid) in a yield of 30.47%. MS m / z(ESI):470.1[M+H] + .

[0238] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.4 5(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).

[0239] Reference Example 5

[0240] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0241] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine Reference Example 4a (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), the reaction was heated to 100 ° C and stirred for 3 hours. The reaction mixture was returned to room temperature, and saturated sodium chloride solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Reference Example 5b (1.3 g) in a yield of 57.49%. MS m / z (ESI): 230.1 [M+H] + .

[0242] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Reference Example 5b (72 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL) and the reaction mixture was heated to 130°C and stirred for 48 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was separated by reverse phase HPLC (formic acid system) to obtain 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Reference Example 5 (46 mg) in a yield of 35.4%. MS m / z(ESI):454.1[M+H] + .

[0243] 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).

[0244] Reference Example 6

[0245] 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

[0246] Step 1: To a solution of Reference Example 5b (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 was allowed to warm to room temperature and stirred for 3 hours. Saturated ammonium chloride solution was added to the reaction mixture at 0°C, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 6-(6-fluoropyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one Reference Example 6a (110 mg) in a yield of 58.69%. MS m / z (ESI): 258.1 [M+H]. + .

[0247] Step 2: Under nitrogen, Intermediate 1 (100 mg, 0.41 mmol), Reference Example 6a (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 hours. Saturated sodium chloride solution was added to the reaction solution, 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 obtain 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 Reference Example 6 (32.1 mg) in a yield of 24.50%. MS m / z(ESI):482.3[M+H] + .

[0248] 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).

[0249] Example 1

[0250] 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0251] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 1 was synthesized. MS m / z (ESI): 438.2 [M+H] + .

[0252] 1 H NMR(400MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.66–7.54(m,2H),7.52–7.36(m,2H),7.09(t,1H),7.01(dd,1H),6.91(d d,2H),6.53(d,1H),6.44(d,1H),6.27(td,1H),4.38–4.11(m,2H),2.21–2.09(m,2H),2.03–1.84(m,2H),1.63–1.44(m,2H).

[0253] Example 3

[0254] 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0255] Example 3 can also be obtained by the following method:

[0256] Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 3a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction mixture was heated to 125°C and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added to the reaction mixture, and the mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL x 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 3b (445 mg) in a yield of 67.26%. MS m / z(ESI):177.1[M+H] + .

[0257] Step 2: Dissolve 3b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL). Heat the reaction to 70°C. Add tert-butyl nitrite (458 mg, 4.44 mmol) and stir at 70°C for 1.5 hours. Add saturated ammonium chloride solution to the reaction mixture, extract the aqueous phase with ethyl acetate (20 mL x 2). Combine the organic phases, dry them, and concentrate to remove most of the solvent. Add petroleum ether / ethyl acetate (1 / 1, 10 mL) to the residue, stir at 0°C for 15 minutes, and filter to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 3c (320 mg) in a 51.05% yield. MS m / z (ESI): 240.0 [M+H]. + .

[0258] Step 3: Sodium borohydride (29 mg, 0.76 mmol) was added to a solution of 3c (140 mg, 0.58 mmol) in methanol (4 mL) at 0°C and stirred for 1 hour. Saturated ammonium chloride solution was slowly added dropwise to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-ol 3d (136 mg) in a yield of 96.33%. MS m / z (ESI): 242.0 [M+H] +

[0259] Step 4: Under nitrogen, 3d (66 mg, 0.27 mmol), intermediate 2 (57 mg, 0.21 mmol), Ruphos Pd G4 (18 mg, 0.002 mmol), and sodium tert-butoxide (61 mg, 0.63 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was heated to 130°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, 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'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 3 (1 mg) in a yield of 1.10%. MS m / z(ESI):432.2[M+H] + .

[0260] 1 H NMR(400MHz,DMSO-d6)δ8.49(d,1H),7.92(d,1H),7.61-7.56(m,1H),7.51-7.44(m,1H) ,7.42-7.36(m,1H),7.26(s,1H),6.92(d,1H),6.86-6.81(m,1H),6.57(d,1H),6.53(d,1 H),6.44(d,1H),6.30-6.23(m,1H),5.42(d,1H),4.81-4.69(m,1H),4.39-4.24(m,1H),4 .22-4.09(m,1H),2.20-2.09(m,2H),2.02-1.82(m,2H),1.62-1.43(m,2H),1.34(d,3H).

[0261] Example 4

[0262] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0263] Referring to the synthesis method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 4 was synthesized. MS m / z (ESI): 445.2 [M+H] + .

[0264] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.65(d,1H),8.36(d,1H),8.14(d,1H),7.87(dd,1H),7.56(dd,1H),7.27(dd,1H),6.86(td,1H),6.74(d ,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.34–4.22(m,1H),4.20– 4.07(m,1H),2.22–2.06(m,2H),2.00–1.81(m,2H),1.63–1.43(m,2H).

[0265] Example 5

[0266] 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0267] Referring to the synthesis method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 5 was synthesized. MS m / z (ESI): 441.2 [M+H] + .

[0268] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.43(d,1H),8.36(d,1H),8.14(dd,1H),7.87(dd,1H),7.56(dd,1H),7.16(s,1H),6.73–6.62(m,2H ),6.54(t,2H),4.97(s,2H),4.38–4.22(m,1H),4.20–4.07(m,1H),2.34(s,3H),2.22–2.06(m,2H),2.02–1.79(m,2H),1.62–1.38(m,2H).

[0269] Example 6

[0270] 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0271] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 6 was synthesized. MS m / z (ESI): 454.1 [M+H] + .

[0272] 1 H NMR(400MHz, DMSO-d6)δ8.63(d,1H),7.91(d,1H),7.62–7.56(m,1H),7.47(ddd,1H),7.42(s,1H),7.39(dd,1H),7.13(d,1H),6.92(d,1H),6.78–6. 69(m,2H),6.52(d,1H),6.44(dd,1H),6.27(td,1H),4.37–4.25(m,1H),4. 20–4.07(m,1H),2.19–2.08(m,2H),2.00–1.82(m,2H),1.63–1.41(m,2H).

[0273] Example 7

[0274] 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0275] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 7 was synthesized. MS m / z (ESI): 472.2 [M+H] + .

[0276] 1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),7.92(d,1H),7.60(dd,1H),7.51–7.44(m,2H),7.40(dd,1H),6.98–6.87(m,3H),6.52(d,1 H),6.44(dd,1H),6.27(td,1H),4.37–4.26(m,1H),4.22–4.11(m,1H),2.20–2.07(m,2H),2.00–1.82(m,2H),1.61–1.43(m,2H).

[0277] Example 8

[0278] 6'-(((1S,3S)-3-((7-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0279] Step 1: Dissolve tert-butyl nitrite (1.45 g, 14.08 mmol) and copper bromide (3.15 g, 14.08 mmol) in acetonitrile (50 mL) at room temperature and stir. Warm the reaction mixture to 70°C. Add 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 8a (2.0 g, 9.39 mmol) portionwise and continue stirring for 2 hours. Concentrate the reaction mixture, and the residue is separated by silica gel column chromatography (eluent system B) to afford 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine 8b (2.5 g) in a 96.2% yield. MS m / z (ESI): 275.9 [M+H] + .

[0280] Step 2: Under nitrogen protection, 8b (500 mg, 1.81 mmol), 3-hydroxyazetidine hydrochloride (989 mg, 1.07 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (163.7 mg, 0.18 mmol) and cesium carbonate (1.76 g, 5.42 mmol) were dissolved in 1,4-dioxane (20 mL), heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)azetidine-3-hydroxy 8c (100 mg) in a 20.6% yield. MS m / z (ESI): 269.0 [M+H] + .

[0281] Step 3: Under nitrogen protection, 8c (100 mg, 0.372 mmol), intermediate 2 (100.5 mg, 0.372 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (35 mg, 0.074 mmol) and cesium carbonate (363 mg, 1.11 mmol) were dissolved in 1,4-dioxane (10 mL) and heated to 130 °C with stirring for 16 h. The reaction mixture was concentrated and purified by preparative HPLC (ammonium bicarbonate system) to give the desired product, 6'-(((1S,3S)-3-((7-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 8 (10 mg), in a 5.87% yield. MS m / z (ESI): 459.2 [M+H] + .

[0282] 1 H NMR(400MHz,DMSO-d6)δ8.14(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7.4 1(dd,1H),6.97(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H),6.2 7(td,1H),6.17(d,1H),5.60(d,1H),4.53(m,1H),4.37-4.26(m,1H),4.10(t,2H), 3.90(d,1H),3.67(d,2H),2.22-2.14(m,2H),1.93-1.90(m,2H),1.55-1.51(m,2H).

[0283] Example 9

[0284] 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0285] Referring to the synthesis method of Example 8, the target product 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 9 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0286] 1 H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H), 7.41(dd,1H),6.98(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H ),6.27(td,1H),6.18(d,1H),5.52(d,1H),4.33(t,1H),3.95-3.86(m,1H),3.8 2-3.74(m,4H),2.24-2.10(m,2H),1.91(t,2H),1.57-1.48(m,2H),1.41(s,3H).

[0287] Example 11

[0288] 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0289] Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 11a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction mixture was heated to 125°C and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added to the reaction mixture, followed by stirring for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL x 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 11b (445 mg) in a yield of 67.26%. MS m / z(ESI):177.1[M+H] + .

[0290] Step 2: Dissolve 11b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL) and heat to 70°C with stirring. Tert-butyl nitrite (458 mg, 4.44 mmol) was added to the reaction mixture, and the reaction was stirred at 70°C for 1.5 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated to remove most of the solvent. To the residue was added PE / EA (1 / 1, 10 mL), and the mixture was stirred at 0°C for 15 minutes. Filtering afforded 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 11c (320 mg) in a 51.05% yield. MS m / z (ESI): 240.0 [M+H]. + .

[0291] Step 3: To a solution of 11c (80 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added methylmagnesium bromide (1 M, 0.7 mL) dropwise at 0°C. The reaction was allowed to warm to room temperature and stirred for 1 hour. Saturated sodium chloride solution was added to the reaction mixture at 0°C, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)propan-2-ol 11d (60 mg) in a yield of 70.30%. MS m / z (ESI): 256.0 [M+H]. + .

[0292] Step 4: Under nitrogen, 11d (50 mg, 0.2 mmol), intermediate 2 (63 mg, 0.23 mmol), Ruphos Pd G4 (17 mg, 0.02 mmol), and sodium tert-butoxide (56 mg, 0.59 mmol) were dissolved in dioxane (1 mL) and stirred at 130°C for 16 hours. The reaction mixture was cooled to room temperature and saturated sodium chloride solution was added. The aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to afford 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 11 (8.7 mg) in a 10.00% yield. MS m / z(ESI):446.2[M+H] + .

[0293] 1H NMR(400MHz,DMSO-d6)δ8.47(d,1H),7.92(d,1H),7.63-7.57(m,1H),7.50 -7.44(m,1H),7.42-7.37(m,1H),7.35(d,1H),6.98-6.86(m,2H),6.60-6.4 9(m,2H),6.44(d,1H),6.31-6.21(m,1H),5.27(s,1H),4.35-4.26(m,1H),4 .20-4.10(m,1H),2.22-2.07(m,2H),2.02-1.80(m,2H),1.62-1.37(m,8H).

[0294] Example 12

[0295] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0296] Referring to the synthesis method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 12 was synthesized. MS m / z (ESI): 495.2 [M+H] + .

[0297] 1 H NMR(400MHz,DMSO-d6)δ8.85–8.74(m,2H),8.36(d,1H),8.14(dd,1H),7.91–7.83(m,2H),7.56(dd,1H),7.15(dd,1H),7.04 (d,1H),6.69(d,1H),6.55(d,1H),4.97(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).

[0298] Example 13

[0299] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[0300] Example 13 can also be prepared according to the following method:

[0301] Step 1: Under nitrogen, 2-fluoro-5-iodopyridine 13a (2 g, 8.97 mmol), 3-pyridazinone (948.00 mg, 9.87 mmol), cuprous iodide (342 mg, 1.79 mmol), trans-(1S,2S)-N,N'-dimethylcyclohexanediamine (255 mg, 1.79 mmol), and potassium carbonate (2.48 g, 17.94 mmol) were dissolved in dimethyl sulfoxide (30 mL) and heated to 130°C with stirring for 16 hours. The reaction mixture was filtered, diluted with saturated sodium chloride solution, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-(6-fluoropyridin-3-yl)pyridazin-3(2H)-one 13b (856 mg) in a yield of 49.93%. MS m / z (ESI): 192.0 [M+H]. + .

[0302] Step 2: Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 13c (710 mg, 3.29 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (856 mg, 4.27 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (228 mg, 0.39 mmol) and cesium carbonate (3.21 g, 9.86 mmol) were dissolved in 1,4-dioxane (25 mL) and the reaction was heated to 130 ° C and stirred for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to give tert-butyl ((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)carbamate 13d (473 mg) in a yield of 42.91%. MS m / z (ESI): 336.2 [M+H] + .

[0303] Step 3: To a solution of 13d (473 mg, 1.41 mmol) in dichloromethane (4 mL) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (3.53 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved with a small amount of dichloromethane and methanol. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline. The mixture was concentrated, and the residue was separated by silica gel column chromatography to afford (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 13e (310 mg) in a 93.43% yield. MS m / z (ESI): 236.1 [M+H]+

[0304] Step 4: Under nitrogen, 13e (74 mg, 0.31 mmol), 13b (50 mg, 0.26 mmol), and diisopropylethylamine (101 mg, 0.78 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) and the reaction mixture was heated to 130°C with stirring for 48 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC to afford 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one 13 (16.8 mg) in a 15.80% yield. MS m / z (ESI): 407.1 [M+H] + .

[0305] 1 H NMR(400MHz,DMSO-d6)δ8.69-8.62(m,1H),8.10(d,1H),8.04-7.98(m,1H),7 .55-7.49(m,1H),7.48-7.43(m,1H),7.30-7.23(m,1H),7.05-6.99(m,1H),6 .94(d,1H),6.89-6.82(m,1H),6.75(d,1H),6.53(d,1H),4.39-4.26(m,1H), 4.22-4.07(m,1H),2.21-2.09(m,2H),2.01-1.83(m,2H),1.63-1.42(m,2H).

[0306] Example 14

[0307] 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0308] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 14 was synthesized. MS m / z (ESI): 402.2 [M+H] + .

[0309] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd,1H),7.39(dd,1H),7.28(d,2H),6.92(d,1H),6.53(d,2H),6 .44(d,1H),6.26(td,1H),4.36–4.26(m,1H),4.22–4.08(m,1H),2.27(s,3H),2.20–2.09(m,2H),1.99–1.82(m,2H),1.59–1.44(m,2H).

[0310] Example 15

[0311] 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0312] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 15 was synthesized. MS m / z (ESI): 424.2 [M+H] + .

[0313] 1 H NMR(400MHz,DMSO-d6)δ9.22(dd,1H),8.15(s,1H),7.91(d,1H),7.63–7.54(m,2H),7.47(ddd,1H),7.39(dd,1H),6.92(d,1H),6.80(d,1H),6 .52(d,1H),6.47–6.41(m,1H),6.27(td,1H),4.38–4.26(m,1H),4.20– 4.08(m,1H),2.20–2.08(m,2H),2.03–1.83(m,2H),1.63–1.42(m,2H).

[0314] Example 18

[0315] 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0316] Referring to the synthesis method of Reference Example 1, 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 18 was synthesized. MS m / z (ESI): 418.2 [M+H] + .

[0317] 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),6.91(d,1H),6.81(d,1H),6.55–6.41 (m,4H),6.26(td,1H),4.37–4.25(m,1H),4.19–4.05(m,1H),3.82(s,3H),2.20–2.07(m,2H),2.01–1.82(m,2H),1.61–1.43(m,2H).

[0318] Example 19

[0319] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0320] Example 19 can also be prepared according to the following method:

[0321] Step 1: Under nitrogen, 13e (48 mg, 0.2 mmol), Reference Example 6a (40 mg, 0.16 mmol), and diisopropylethylamine (60 mg, 0.47 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was heated to 130°C and stirred for 48 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by reverse-phase HPLC to afford 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 19 (7.3 mg) in a 9.94% yield. MS m / z (ESI): 473.3 [M+H]. + .

[0322] 1H NMR(400MHz,DMSO-d6)δ8.80-8.72(m,1H),8.70-8.62(m,1H),8.27-8.19(m,1H),7.85(d,1H),7.69-7.60(m,1H),7.34-7.23(m,2H),6.9 3-6.81(m,2H),6.75(d,1H),6.57(d,1H),4.37-4.26(m,1H),4.22-4.10(m,1H),2.22-2.08(m,2H),2.02-1.84(m,2H),1.64-1.34(m,8H).

[0323] Example 20

[0324] 3-Fluoro-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

[0325] Referring to the synthesis method of Reference Example 2, 3-fluoro-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 20 was synthesized. MS m / z (ESI): 463.2 [M+H] + .

[0326] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.66(dd,1H),8.33(d,1H),8.09(dd,1H),7.85(dd,1H),7.27(dd,1H),6.88-6.84(m,1H),6.74(d,1H),6.71(d ,1H),6.55(d,1H),4.93(s,2H),4.32-4.27(m,1H),4.18-4.13(m,1H),2. 19-2.09(m,2H),2.01-1.93(m,1H),1.90-1.83(m,1H),1.59-1.46(m,2H).

[0327] Example 21

[0328] 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-d]pyrimidin-7-one

[0329] Referring to the synthesis method of Reference Example 2, 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-d]pyrimidin-7-one 21 was synthesized. MS m / z (ESI): 446.2 [M+H] + .

[0330] 1 H NMR(400MHz,DMSO-d6)δ8.86–8.79(m,2H),8.66(dd,1H),8.40(d,1H),7.91(dd,1H ),7.27(dd,1H),6.88–6.81(m,1H),6.74(dd,2H),6.56(d,1H),5.02(s,2H),4.37– 4.23(m,1H),4.21–4.08(m,1H),2.21–2.06(m,2H),1.99–1.83(m,2H),1.62–1.44(m,2H).

[0331] Example 22

[0332] 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-d]pyrimidin-7-one

[0333] Referring to the synthesis method of Reference Example 3, 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-d]pyrimidin-7-one 22 was synthesized. MS m / z (ESI): 496.2 [M+H] + .

[0334] 1H NMR (400MHz, DMSO-d6) δ9.41(s,1H),9.23(s,1H),8.82(d,1H),8.37(d,1H),7.89-7.85(m,2H),7.15(dd,1H),7.04(d,1H),6.80( d,1H),6.57(d,1H),5.02(s,2H),4.34-4.29(m,1H),4.24-4.18(m,1H),2.20-2.13(m,2H),2.01-1.89(m,2H),1.62-1.46(m,2H).

[0335] Example 23

[0336] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(2-hydroxypropan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0337] Referring to the synthesis method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(2-hydroxypropane-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 23 was synthesized. MS m / z (ESI): 503.2 [M+H] + .

[0338] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),8.34(d,1H),8.06(d,1H),7.90( d,1H),7.87-7.81(m,1H),7.30-7.23(m,1H),6.90-6.82(m,1H),6.75(d,1H ),6.69(d,1H),6.56(d,1H),5.40(s,1H),4.88(s,2H),4.37-4.23(m,1H),4 .21-4.07(m,1H),2.21-2.05(m,2H),2.01-1.81(m,2H),1.62-1.39(m,8H).

[0339] Example 25

[0340] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one

[0341] Referring to the synthesis method of Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one 25 was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0342] 1 H 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).

[0343] Example 26

[0344] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one

[0345] Referring to the synthesis method of Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one 26 was synthesized. MS m / z (ESI): 512.1 [M+H] + .

[0346] 1H 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).

[0347] Example 27

[0348] 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

[0349] Referring to the synthesis method of Reference Example 3, 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 27 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0350] 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).

[0351] Example 28

[0352] 3-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one

[0353] The target product 3-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one 28 can also be synthesized by referring to the synthesis method of Reference Example 1. MS m / z (ESI): 407.2 [M+H] + .

[0354] 1 H NMR(400MHz,DMSO-d6)δ8.73-8.58(m,1H),8.39(s,1H),8.01-7.90(m,2H),7.48-7.40(m,1H),7.30-7.23(m,1H),7.03(d,1H),6.90-6.82(m ,1H),6.75(d,1H),6.55(d,1H),6.47(d,1H),4.39-4.26(m,1H),4.24- 4.09(m,1H),2.21-2.08(m,2H),2.02-1.80(m,2H),1.65-1.40(m,2H).

[0355] Example 29

[0356] 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazin-2(1H)-one

[0357] The target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazin-2(1H)-one 29 can also be synthesized by referring to the synthesis method of Reference Example 1. MS m / z (ESI): 407.1 [M+H] + .

[0358] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.61(m,1H),8.07(s,1H),8.02(d,1H),7.63(d,1H),7.52-7.45(m,1H),7.36(d,1H),7.31-7.23(m,1H),7.04(d,1 H),6.90-6.81(m,1H),6.75(d,1H),6.55(d,1H),4.39-4.26(m,1H),4.2 2-4.10(m,1H),2.21-2.06(m,2H),2.02-1.80(m,2H),1.64-1.42(m,2H).

[0359] Example 31

[0360] 6'-(3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridyl]-2(1H)-one

[0361] Example 31 can also be prepared according to the following method:

[0362] Step 1: Under nitrogen protection, (1S,3S)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (200 mg, 0.9 mmol), 5-bromo-2-fluoropyridine (195 mg, 1.1 mmol) and N,N-diisopropylethylamine (330 mg, 2.6 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the reaction temperature was raised to 130 ° C and stirred for 16 hours. The reaction was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to obtain N 1 -(5-bromopyridin-2-yl)-N 3 -(7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 31a (200 mg), yield: 60%. MS m / z (ESI): 391.0 [M+H] + .

[0363] Step 2: Under nitrogen, 31a (170 mg, 0.4 mmol), (2-oxo-1H-pyridin-3-yl)boronic acid (60 mg, 0.4 mmol), and sodium carbonate (92 mg, 0.9 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (64 mg, 0.1 mmol) was added, and the reaction was heated to 80°C and stirred for 1 hour. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 6'-(3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridyl]-2(1H)-one 31 (90 mg) in a 51% yield. MS m / z (ESI): 406.1 [M+H] + .

[0364] 1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.66(dd,1H),8.34(d,1H),7.77(dd,1H),7.54(dd,1H),7.31–7.24(m,2H),6.86 (td,1H),6.71(dd,2H),6.46(d,1H),6.23(t,1H),4.31(q,1H),4.15(d,1H),2.13(dt,2H),1.91(dd,2H),1.52(dd,2H).

[0365] Example 32

[0366] 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridinyl]-2-one

[0367] Step 1: Under nitrogen protection, Reference Example 2c (100 mg, 0.43 mmol), 2-fluoro-5-iodo-pyridine (142 mg, 0.64 mmol) and diisopropylethylamine (165 mg, 1.28 mmol) were dissolved in dimethyl sulfoxide (1.8 mL). The reaction was heated to 130°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and ethyl acetate (25 mL × 2) was used for extraction. The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain (1S,3S)-N 1 -(7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine 32a (95 mg), yield: 51.00%. MS m / z (ESI): 439.0 [M+H] + .

[0368] Step 2: Under nitrogen protection, 32a (50 mg, 0.11 mmol), 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (35 mg, 0.23 mmol), cuprous iodide (22 mg, 0.11 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (16 mg, 0.11 mmol) and cesium carbonate (112 mg, 0.34 mmol) were dissolved in 1,4-dioxane (1 mL) and the reaction was heated to 105 °C with stirring for 2 h. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to give 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one 32 (25.1 mg) in a yield of 47.46%. MS m / z (ESI): 464.2 [M+H]. + .

[0369] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),7.91(d,1H),7.65-7.59(m,1H),7.5 6-7.52(m,1H),7.42-7.37(m,1H),7.30-7.24(m,1H),6.91(d,1H),6.89-6.83(m ,1H),6.75(d,1H),6.53(d,1H),6.34-6.28(m,1H),5.33(s,1H),4.38-4.24(m,1 H),4.22-4.09(m,1H),2.22-2.07(m,2H),2.04-1.81(m,2H),1.64-1.37(m,8H).

[0370] Example 33

[0371] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-methyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0372] Referring to the synthesis method of Reference Example 2, the target product 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-methyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 33 was synthesized. MS m / z (ESI): 460.2 [M+H] + .

[0373] 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.65(dd,1H),8.36(d,1H),7.87(dd,1H),7.27(dd,1H),6.86(td,1H),6.75(dd,2H), 6.56(d,1H),4.96(s,2H),4.30(q,1H),4.15(q,1H),2.76(s,3H),2.19-2.09(m,2H),2.00-1.83(m,2H),1.59-1.46(m,2H).

[0374] Example 49

[0375] 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

[0376] Step 1: To a solution of 2-bromo-6-tert-butylpyridine 49a (300 mg, 1.40 mmol) in tetrahydrofuran (5 mL) at -78°C was added lithium diisopropylamide (2M, 1.05 mL). The reaction was stirred at -78°C for 1 hour, and then N,N-dimethylformamide (410 mg, 5.60 mmol) was added dropwise. The reaction 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 x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-bromo-6-(tert-butyl)nicotinaldehyde 49b (56 mg) in a yield of 16.51%. MS m / z (ESI): 242.0 [M+H]. + .

[0377] Step 2: Under carbon monoxide protection, 49b (53 mg, 0.22 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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). The reaction mixture was heated to 80°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford methyl 6-(tert-butyl)-3-formylpicolinate 49c (13 mg) in a yield of 26.84%. MS m / z (ESI): 222.1 [M+H]. + .

[0378] Step 3: Dissolve Reference Example 2e (23 mg, 0.07 mmol), 49c (13 mg, 0.06 mmol), and acetic acid (5 mg, 0.09 mmol) in 1,2-dichloroethane (2 mL). Heat the reaction to 60°C and stir for 1 hour. After the reaction mixture returns to room temperature, sodium triacetoxyborohydride (62 mg, 0.29 mmol) is added and stirred for 15 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried, and concentrated. 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 49 (15.8 mg) in a yield of 53.72%. MS m / z (ESI): 501.2 [M+H] + .

[0379] 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).

[0380] Example 50

[0381] 2-(6-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0382] Referring to the synthesis method of Reference Example 2, 2-(6-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 50 was synthesized. MS m / z (ESI): 461.1 [M+H] + .

[0383] 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.66(dd,1H),8.32(d,1H),7.80(dd,1H),7.55(d,1H),7.27(dd,1H),6.86(td,J=7.6,2.8Hz,1H ),6.74(d,J=7.3Hz,1H),6.67(d,1H),6.50(dd,2H),4.73(s,2H),4.28(q,1H),4.15(q,1H),2.14(dq,2H),1.90(dq,2H),1.51(dd,2H).

[0384] Example 51

[0385] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0386] Step 1: Dissolve 5-amino-2-bromo-pyridine-4-carboxylic acid methyl ester (10 g, 43.28 mmol) and N-bromosuccinimide (8.47 g, 47.61 mmol) in 1,2-dichloroethane (70 mL) at room temperature and stir for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to afford 3-amino-2,6-dibromo-pyridine-4-carboxylic acid methyl ester 51a (12.5 g) in a 93.18% yield. MS m / z (ESI): 308.9, 310.9, 312.9 [M+H] + .

[0387] Step 2: Under nitrogen, 51a (12.4 g, 40.01 mmol), a 3.5 M solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborin in tetrahydrofuran (23 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.91 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (1.83 g, 2.0 mmol), and potassium phosphate (17.0 g, 80.01 mmol) were dissolved in 1,4-dioxane (100 mL). The mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system B) to afford methyl 3-amino-2,6-dimethylisonicotinate 51b (5 g) in a yield of 69.35%. MS m / z(ESI):181.1[M+H] + .

[0388] Step 3: Dissolve 51b (4.8 g, 26.64 mmol) and copper bromide (2.97 g, 13.32 mmol) in acetonitrile (80 mL) at room temperature, and add tert-butyl nitrite (8.24 g, 79.91 mmol) dropwise to the reaction mixture. Stir the reaction at room temperature for 30 minutes, then heat to 60°C and stir for 1 hour. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to afford methyl 3-bromo-2,6-dimethylisonicotinate 51c (4.9 g) in a yield of 75.37%. MS m / z (ESI): 244.0, 246.0 [M+H]. + .

[0389] Step 4: Under nitrogen, 51c (500 mg, 2.05 mmol), potassium tert-butoxymethyl trifluoroborate (795.0 mg, 4.10 mmol), tris(dibenzylideneacetone)dipalladium (187.6 mg, 0.20 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (191.2 mg, 0.41 mmol), and sodium carbonate (651.4 mg, 6.15 mmol) were dissolved in a mixture of toluene (13 mL) and water (0.5 mL). The reaction mixture was heated to 120°C and stirred for 16 hours. The reaction solution was diluted with dichloromethane (40 mL), the organic phase was washed with water, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to afford methyl 3-(tert-butoxymethyl)-2,6-dimethylisonicotinate 51d (300 mg) in a yield of 58.27%. MS m / z(ESI):252.0[M+H] + .

[0390] Step 5: Dissolve 51d (300 mg, 1.19 mmol) in dichloromethane (7 mL) at room temperature. Trifluoroacetic acid (409.02 mg, 3.59 mmol) was added dropwise to the reaction mixture and stirred for 1 hour. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate solution and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give 4,6-dimethylfuro[3,4-c]pyridin-1(3H)-one 51e (120 mg) in a yield of 61.61%. MS m / z (ESI): 164.1 [M+H]. + .

[0391] Step 6: Under nitrogen, Reference Example 2e (70 mg, 0.21 mmol) and 51e (69.8 mg, 0.43 mmol) were dissolved in 1,4-dioxane (5 mL). A 2M solution of trimethylaluminum in toluene (0.43 mL) was added dropwise to the reaction mixture, which was heated to 90°C and stirred for 1 hour. The reaction mixture was added dropwise to methanol (10 mL) with stirring, and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(hydroxymethyl)-2,6-dimethylisonicotinamide 51f (30 mg) in a yield of 28.6%. MS m / z (ESI): 491.2 [M+H]. + .

[0392] Step 7: 51f (20 mg, 0.04 mmol) and triphenylphosphine (21.4 mg, 0.08 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature. Diisopropyl azodicarboxylate (16.5 mg, 0.08 mmol) was added and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative HPLC (NH4 bicarbonate system) to give 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 51 (1.2 mg) in a yield of 6.23%. MS m / z (ESI): 473.2 [M+H] + .

[0393] 1H NMR(400MHz,DMSO-d6)δ8.69–8.62(m,1H),8.36(d,1H),7.86(dd,1H),7.40(s,1H),7.27(dd,1H),6.86(td,1H),6.72(dd,2H),6.5 4(d,1H),4.93(s,2H),4.32–4.23(m,1H),4.18–4.10(m,1H),2.55(s,6H),2.19–2.07(m,2H),1.99–1.82(m,2H),1.60–1.45(m,2H).

[0394] Example 52

[0395] 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)piperidin-2-one

[0396] Referring to the synthesis method of Example 32, the target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)piperidin-2-one 52 was synthesized. MS m / z (ESI): 410.2 [M+H] + .

[0397] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.60(m,1H),7.81(d,1H),7.31-7.20(m,2H),6.90-6.81(m,1H),6.73(d,1H),6.60(d,1H),6.44(d,1H), 4.31-4.20(m,1H),4.19-4.08(m,1H),3.56-3.43(m,2H),2.40-2.27(m,2H),2.20-2.04(m,2H),2.01-1.72(m,6H),1.64-1.37(m,2H).

[0398] Example 53

[0399] 4-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)morpholin-3-one

[0400] The target product 4-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)morpholin-3-one 53 was synthesized by referring to the synthesis method of Example 32. MS m / z (ESI): 412.2 [M+H] + .

[0401] 1 H NMR (400MHz, DMSO-d6) δ8.71-8.61(m,1H),7.92(d,1H),7.37-7.31(m,1H),7.30-7.23(m,1H),6.90-6.82(m,1H),6.77-6.67(m,2H),6.47(d ,1H),4.32-4.21(m,1H),4.20-4.08(m,3H),3.98-3.88(m,2H),3.67- 3.57(m,2H),2.19-2.06(m,2H),1.99-1.79(m,2H),1.63-1.39(m,2H).

[0402] Example 54

[0403] 5-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2.4]heptan-4-one

[0404] Referring to the synthesis method of Example 32, the target product 5-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2.4]heptan-4-one 54 was synthesized. MS m / z (ESI): 422.2 [M+H] + .

[0405] 1H NMR(400MHz,DMSO-d6)δ8.69-8.61(m,1H),8.11(d,1H),7.74-7.64(m,1H), 7.31-7.21(m,1H),6.90-6.81(m,1H),6.73(d,1H),6.53(d,1H),6.47(d,1H ),4.30-4.20(m,1H),4.19-4.08(m,1H),3.81(t,2H),2.22-2.05(m,4H),1. 99-1.77(m,2H),1.62-1.37(m,2H),0.95--0.89(m,2H),0.85-0.79(m,2H).

[0406] Example 55

[0407] 6-(6-(((1S,3S)-3-((7-cyclopropyl-[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

[0408] Referring to the synthesis method of Reference Example 3, 6-(6-(((1S,3S)-3-((7-cyclopropyl-[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 55 was synthesized. MS m / z (ESI): 467.2 [M+H] + .

[0409] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.44–8.31(m,2H),8.10(d,1H),7.87(dd,1H),7.61(dd,1H),7.06(s,1H),6.72–6.43(m,4H) ,4.92(s,2H),4.32–4.23(m,1H),4.18–4.10(m,1H),2.23–2.07(m,2H),2.05–1.81(m,4H),1.62–1.40(m,3H),1.37–1.26(m,2H).

[0410] Example 56

[0411] 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[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

[0412] Referring to the synthesis method of Reference Example 3, 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[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 56 was synthesized. MS m / z (ESI): 493.2 [M+H] + .

[0413] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.63(d,1H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.65–7.58(m,1H),7.42(t,1H),7.14(d,1H),6 .78–6.66(m,3H),6.55(d,1H),4.92(s,2H),4.32–4.23(m,1H),4.20– 4.07(m,1H),2.20–2.08(m,2H),2.01–1.82(m,2H),1.60–1.43(m,2H).

[0414] Example 56 can also be synthesized by the following method:

[0415] Step 1: Under nitrogen, dissolve 2-bromo-7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.95 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (227.6 mg, 1.14 mmol), cesium carbonate (617.0 mg, 1.89 mmol), tris(dibenzylideneacetone)palladium (173.4 mg, 0.19 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (219.2 mg, 0.38 mmol) in 1'4-dioxane (10 mL) and microwave-heat at 130°C for 2 hours. Filter the reaction mixture, and concentrate the filtrate. The residue was purified by silica gel column chromatography (elution system B) to give tert-butyl N-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]carbamate 56a (170 mg) in a 46.8% yield. MS m / z (ESI): 384.2 [M+H] + .

[0416] Step 2: Dissolve 56a (170 mg, 0.44 mmol) in methanol (7 mL) at room temperature, add hydrochloric acid (4 M, 4 mL), and stir for half an hour. The reaction mixture was concentrated, and the residue was diluted with methanol. The mixture was adjusted to pH 8-10 with saturated sodium bicarbonate solution. After concentration, the residue was purified by silica gel column chromatography (elution system A) to give (1S,3S)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine 56b (120 mg) in a yield of 95.5%. MS m / z (ESI): 284.2 [M+H] + .

[0417] Step 3: Dissolve 56b (140 mg, 0.49 mmol), 2-fluoro-5-nitro-pyridine (77.2 mg, 0.54 mmol), and cesium carbonate (322.0 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL) at room temperature and heat to 80°C with stirring for 3 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography (elution system A) to afford (1S,3S)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N1-(5-nitro-2-pyridinyl)cyclopentane-1,3-diamine 56c (50 mg) in a 25.0% yield. MS m / z (ESI): 406.2 [M+H] + .

[0418] Step 4: Under a hydrogen atmosphere, 56c (50 mg, 0.12 mmol) and palladium on carbon (13.1 mg, 0.012 mmol, purity: 10%) were dissolved in methanol (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to afford N2-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridine-2,5-diamine 56d (35 mg) in a 75.6% yield. MS m / z (ESI): 376.1 [M+H] + .

[0419] Step 5: 56d (35 mg, 0.09 mol), methyl 3-(bromomethyl)pyridine-2-carboxylate (20.0 mg, 0.065 mmol), and N,N-diisopropylethylamine (36.1 mg, 0.28 mmol) were dissolved in tert-butanol (5 mL) at room temperature and stirred at 50°C for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative thin-layer chromatography (elution system A) to give 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[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 56 (11 mg) in a 24.0% yield. MS m / z(ESI):493.2[M+H] + .

[0420] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.63(d,1H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.65–7.58(m,1H),7.42(t,1H),7.14(d,1H),6 .78–6.66(m,3H),6.55(d,1H),4.92(s,2H),4.32–4.23(m,1H),4.20– 4.07(m,1H),2.20–2.08(m,2H),2.01–1.82(m,2H),1.60–1.43(m,2H).

[0421] Example 57

[0422] 4-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

[0423] Step 1: Reference Example 3g (100 mg, 0.26 mmol), methyl 3-(bromomethyl)-2-chloroisonicotinate (74.8 mg, 0.21 mmol) and N,N-diisopropylethylamine (102.7 mg, 0.79 mmol) were dissolved in a mixed solvent of tert-butanol (5 mL) and N,N-dimethylformamide (2 mL) at room temperature and stirred for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (elution system A) to afford 4-chloro-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 57a (90 mg) in a 64.21% yield. MS m / z (ESI): 529.1 [M+H]. + .

[0424] Step 2: Under nitrogen, 57a (90 mg, 0.17 mmol), a tetrahydrofuran solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborin (3.5 M, 0.15 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16.2 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium (15.6 mg, 0.017 mmol) and potassium phosphate (72.24 mg, 0.340 mmol) were dissolved in 1,4-dioxane (8 mL), heated to 100 °C and stirred for 5 h. The reaction mixture was concentrated, and the residue was purified by thin-layer chromatography (elution system A) to afford 4-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 57 (56.6 mg) in a 65.41% yield. MS m / z (ESI): 509.1 [M+H]. + .

[0425] 1 H NMR (400MHz, DMSO-d6) δ8.82(d,1H),8.63(d,1H),8.38(d,1H),7.91–7.82(m,2H),7.54(d,1H),7.15(dd,1H),7.03(d,1H),6. 73(s,1H),6.57(d,1H),4.98(s,2H),4.37–4.14(m,2H),2.57(s,3H),2.21–2.10(m,2H),2.03–1.86(m,2H),1.64–1.44(m,2H).

[0426] Example 58

[0427] 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridine-3-yl

[0428] yl)-5-azaspiro[2.4]heptan-4-one

[0429] Step 1: To a solution of p-toluenesulfonic acid (96 mg, 0.56 mmol) in acetonitrile (1.5 mL) was added Reference Example 3g (70 mg, 0.19 mmol). The reaction mixture was cooled to 0°C. A solution of sodium nitrite (26 mg, 0.37 mmol) and potassium iodide (80 mg, 0.48 mmol) in water (0.5 mL) was added. The reaction mixture was warmed to room temperature and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford (1S,3S)-N1-(5-iodopyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 58a (37 mg) in a yield of 40.85%. MS m / z(ESI):489.1[M+H] + .

[0430] Step 2: Referring to the synthesis method of Example 32, 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2.4]heptan-4-one 58 was synthesized. MS m / z (ESI): 472.2 [M+H] + .

[0431] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.11(d,1H),7.85(s,1H),7.74-7.64(m,1H),7.19-7.10(m,1H),7.02(d,1H),6.54(d,1H),6.47(d,1 H),4.32-4.11(m,2H),3.87-3.74(m,2H),2.23-2.07(m,4H),2.00-1.80(m,2H),1.65-1.38(m,2H),0.95-0.90(m,2H),0.85-0.79(m,2H).

[0432] Example 59

[0433] 4,6-Dimethyl-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

[0434] Referring to the synthesis method of Reference Example 3, 4,6-dimethyl-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 59 was synthesized. MS m / z (ESI): 523.2 [M+H] + .

[0435] Example 60

[0436] 3-Methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)

[0437] Pyridin-3-yl)methylpicolinamide

[0438] Step 1: Dissolve Reference Example 3g (50 mg, 0.13 mmol), 3-methyl-2-pyridinecarboxylic acid (20 mg, 0.15 mmol) and N-methylimidazole (33 mg, 0.4 mmol) in acetonitrile (1.5 mL). Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.2 mmol) to the reaction mixture and stir at room temperature for 2 hours. Saturated sodium chloride solution (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to give 3-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpicolinamide 60 (9.7 mg) in a yield of 14.75%. MS m / z (ESI): 497.2 [M+H]. + .

[0439] 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.82(d,1H),8.51(d,1H),8.33(d,1H),7.85(s,1H),7.82-7.75(m,2H),7.53-7.44(m,1H),7.18- 7.11(m,1H),7.03(d,1H),6.52-6.43(m,2H),4.33-4.13(m,2H),2.56(s,3H),2.21-2.08(m,2H),2.01-1.82(m,2H),1.64-1.41(m,2H).

[0440] Example 61

[0441] 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)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0442] Referring to the synthesis method of Reference Example 3, 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)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 61 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0443] 1 H NMR(400MHz,DMSO-d6)δ8.87–8.76(m,2H),8.36(d,1H),8.10(dd,1H),7.86(dd,2H),7.15(dd,1H),7.02(d,1H),6 .71(d,1H),6.55(d,1H),4.96(d,2H),4.38–4.12(m,2H),2.24–2.10(m,2H),2.05–1.83(m,2H),1.63–1.42(m,2H).

[0444] Example 62

[0445] N-Methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpicolinamide

[0446] Step 1: 2-Fluoro-5-aminopyridine 62a (500 mg, 4.46 mmol), pyridine-2-carboxylic acid (604 mg, 4.91 mmol), and N-methylimidazole (1.10 g, 13.38 mmol) were dissolved in acetonitrile (15 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.88 g, 6.69 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. Saturated sodium chloride solution (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, and concentrated. Petroleum ether / ethyl acetate (v / v = 1 / 1, 10 mL) was added to the residue and stirred at 60°C for 30 minutes. After cooling to room temperature, the mixture was filtered to obtain N-(6-fluoropyridin-3-yl)methylpicolinamide 62b (464 mg) in a yield of 47.90%. MS m / z(ESI):218.1[M+H] + .

[0447] Step 2: To a solution of 62b (464 mg, 2.14 mmol) in tetrahydrofuran (10 mL) at 0°C was added sodium hydride (128 mg, 3.20 mmol, 60% content). After 30 minutes, iodomethane (606 mg, 4.27 mmol) was added to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 1.5 hours. Saturated sodium chloride solution (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography to afford N-(6-fluoropyridin-3-yl)-N-methylpicolinamide 62c (53 mg) in a yield of 10.73%. MS m / z (ESI): 232.1 [M+H] + .

[0448] Step 3: Reference Example 3e (68 mg, 0.18 mmol), 62c (54 mg, 0.23 mmol), and N,N-diisopropylethylamine (69 mg, 0.54 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was heated to 130°C and stirred for 60 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC to obtain N-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpicolinamide 62 (4.2 mg) in a yield of 4.73%. MS m / z (ESI): 497.2 [M+H]. + .

[0449] 1H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.33(d,1H),7.84(s,1H),7.76-7.68(m,1H),7.63(s,1H),7.40(d,1H),7.27-7.19(m,2H),7.17-7.1 1(m,1H),6.96(d,1H),6.60(d,1H),6.29(d,1H),4.22-4.05(m,2H),3 .29(s,3H),2.13-2.01(m,2H),1.93-1.70(m,2H),1.60-1.31(m,2H).

[0450] Example 63

[0451] 3-(2-Hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0452] Referring to the synthesis method of Example 58, 3-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 63 was synthesized. MS m / z (ESI): 514.2 [M+H] + .

[0453] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),7.91(d,1H),7.85(s,1H),7.50(d,1H), 7.42-7.35(m,1H),7.18-7.12(m,1H),7.02(d,1H),6.89(d,1H),6.52(d,1H), 6.46(d,1H),6.38-6.33(m,1H),5.15(s,1H),4.40-4.28(m,1H),4.27-4.15( m,1H),2.23-2.09(m,2H),2.03-1.84(m,2H),1.65-1.44(m,2H),1.38(s,6H).

[0454] Example 65

[0455] 5-Carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile

[0456] Referring to the synthesis method of Reference Example 3, 5-carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile 65 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0457] 1 H NMR(400MHz,DMSO-d6)δ9.24(d,1H),8.82(d,1H),8.71(d,1H),8.37(d,1H),7.87(dd,1H),7.85(s,1H),7.15(dd,1H),7.03(d,1H),6 .74(d,1H),6.56(d,1H),5.09(s,2H),4.34-4.29(m,1H),4.23-4.18(m,1H),2.18-2.12(m,2H),2.01-1.88(m,2H),1.59-1.49(m,2H).

[0458] Example 66

[0459] 1-Carbonyl-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]pyridine-6-carbonitrile

[0460] Referring to the synthesis method of Reference Example 3, 1-carbonyl-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]pyridine-6-carbonitrile 66 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0461] 1H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.82(d,1H),8.41(s,1H),8.35(d,1H),7.86-7.82(m,2H),7.15(dd,1H),7.01(d,1H),6.77( d,1H),6.57(d,1H),5.12(s,2H),4.34-4.29(m,1H),4.24-4.19(m,1H),2.20-2.13(m,2H),2.00-1.88(m,2H),1.61-1.50(m,2H).

[0462] Example 67

[0463] 2-Methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0464] Referring to the synthesis method of Reference Example 3, 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 67 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0465] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.35(d,1H),8.01(d,1H),7.91-7.78(m,2H),7.42(d,1H),7.14(d,1H),7.01(d,1H),6.64(d,1H), 6.55(d,1H),4.90(s,2H),4.33-4.27(m,1H),4.23-4.18(m,1H),2.62(s,3H),2.18-2.13(m,2H),2.00-1.89(m,2H),1.60-1.49(m,2H).

[0466] Example 68

[0467] 2-Cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0468] Referring to the synthesis method of Reference Example 3, 2-cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 68 was synthesized. MS m / z (ESI): 535.2 [M+H] + .

[0469] 1 H NMR (400MHz, DMSO-d6) δ8.82(d,1H),8.32(d,1H),7.96(d,1H),7.88-7.83(m,2H),7.46(d,1H),7.14(dd,1H),7.02(d,1H),6.63(d,1H),6. 53(d,1H),4.85(s,2H),4.32-4.18(m,2H),2.31-2.25(m,1H),2.18-2 .12(m,2H),2.01-1.85(m,2H),1.61-1.47(m,2H),1.10-1.01(m,4H).

[0470] Example 69

[0471] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octan-5-yl)pyridin-2-yl)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0472] Referring to the synthesis method of Example 58, (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octan-5-yl)pyridin-2-yl)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 69 was synthesized. MS m / z (ESI): 424.2 [M+H] + .

[0473] Example 70

[0474] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octan-5-yl)pyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0475] Referring to the synthesis method of Example 58, (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octan-5-yl)pyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 70 was synthesized. MS m / z (ESI): 474.2 [M+H] + .

[0476] Example 71

[0477] 6-Cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0478] Referring to the synthesis method of Reference Example 3, 6-cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 71 was synthesized. MS m / z (ESI): 535.2 [M+H] + .

[0479] Example 72

[0480] 3-Carbonyl-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]pyridine-6-carbonitrile

[0481] Referring to the synthesis method of Reference Example 3, 3-carbonyl-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]pyridine-6-carbonitrile 72 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0482] Example 73

[0483] 6'-(((1S,3S)-3-((7-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridyl]-2(1H)-one

[0484] Referring to the synthesis method of Example 31, 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridyl]-2(1H)-one 73 was synthesized. MS m / z (ESI): 456.2 [M+H] + .

[0485] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.81(d,1H),8.35(d,1H),7.84(s,1H),7.77(dd,1H),7.54(dd,1H),7.28(d,1H),7.14(dd,1H),7.00(d ,1H),6.66(d,1H),6.46(d,1H),6.23(t,1H),4.35–4.30(m,1H),4.23– 4.18(m,1H),2.19–2.12(m,2H),2.01-1.88(m,2H),1.61–1.49(d,2H).

[0486] Example 75

[0487] 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)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0488] Referring to the synthesis method of Reference Example 3, 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)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 75 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0489] 1H NMR(400MHz,DMSO-d6)δ8.87–8.76(m,2H),8.36(d,1H),8.10(dd,1H),7.86(dd,2H),7.15(dd,1H),7.02(d,1H),6 .71(d,1H),6.55(d,1H),4.96(d,2H),4.40–4.15(m,2H),2.24–2.10(m,2H),2.05–1.83(m,2H),1.65–1.41(m,2H).

[0490] Example 76

[0491] 1-Carbonyl-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]pyridine-4-carbonitrile

[0492] Referring to the synthesis method of Reference Example 3, 1-carbonyl-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]pyridine-4-carbonitrile 76 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0493] 1 H NMR(400MHz,DMSO-d6)δ8.94(d,1H),8.82(d,1H),8.41(d,1H),8.08(d,1H),7.91-7.81(m,2H),7.18-7.11(m,1H),7.02(d,1H),6.7 8(d,1H),6.57(d,1H),5.25(s,2H),4.38-4.28(m,1H),4.26-4.16(m,1H),2.24-2.10(m,2H),2.05-1.83(m,2H),1.67-1.43(m,2H).

[0494] Example 77

[0495] 3-Carbonyl-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]pyridine-7-carbonitrile

[0496] Referring to the synthesis method of Reference Example 3, 3-carbonyl-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]pyridine-7-carbonitrile 77 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0497] Example 78

[0498] 4-Hydroxy-1-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-2(1H)-one

[0499] Referring to the synthesis method of Example 58, 4-hydroxy-1-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-2(1H)-one 78 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0500] 1 H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.82(d,1H),7.94(d,1H),7.85(s,1H),7.62(d,1H),7.42-7.35(m,1H),7.20-7.10(m,1H),7.03(d,1H) ,6.93(d,1H),6.51(d,1H),5.65-5.56(m,1H),4.38-4.26(m,1H),4.25 -4.14(m,1H),2.21-2.09(m,2H),2.02-1.82(m,2H),1.66-1.40(m,2H).

[0501] Example 79

[0502] 5-(3-(2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0503] Step 1: Under nitrogen, 2-benzyloxy-5-bromopyridine 79a (2.0 g, 7.57 mmol), methyl 3-pyrazolecarboxylate (1.05 g, 8.33 mmol), cuprous iodide (288.4 mg, 1.51 mmol), L-proline (174.4 mg, 1.51 mmol), and potassium carbonate (3.14 g, 22.72 mmol) were dissolved in dimethyl sulfoxide (5 mL). The reaction mixture was heated to 120°C and stirred for 5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system B) to afford methyl 1-(6-(benzyloxy)pyridin-3-yl)-1H-pyrazole-3-carboxylate 79b (230 mg) in a 9.8% yield. MS m / z (ESI): 310.1 [M+H] + .

[0504] Step 2: Under a hydrogen atmosphere, 79b (230 mg, 0.743 mmol) and palladium on carbon (27 mg, 0.223 mmol) were dissolved in methanol (5 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered, dried, and concentrated to afford methyl 1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylate 79c (60 mg) in a 36.8% yield. MS m / z (ESI): 220.1 [M+H] + .

[0505] Step 3: Under nitrogen, 79c (60 mg, 0.123 mmol), (26.9 mg, 0.123 mmol), cuprous iodide (23.4 mg, 0.123 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (17.5 mg, 0.123 mmol) and cesium carbonate (120 mg, 0.368 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction was heated to 100 °C and stirred for 16 h. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution system B) to afford methyl 1-(2-oxo-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-5-yl)-1H-pyrazole-3-carboxylate 79d (60 mg) in an 84.3% yield. MS m / z (ESI): 580.2 [M+H]. + .

[0506] Step 4: Under nitrogen, 79d (60 mg, 0.103 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) at 0°C. Methylmagnesium bromide in tetrahydrofuran (1 M, 0.5 mL) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched with methanol and concentrated. The residue was purified by preparative HPLC (formic acid system) to afford 5-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 79 (10.0 mg) in a 16.7% yield. MS m / z (ESI): 580.2 [M+H]. + .

[0507] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.15(d,1H),8.05-7.95(m,3H),7.85(s,1H),7.48(dd,1H),7.15(dd,1H),7.04(d,1H),6.97(d ,1H),6.58(dd,2H),6.42(d,1H),4.96(s,2H),4.37-4.19(m,2H),2.17(dd,1H),2.03-1.87(m,2H),1.62-1.45(m,2H),1.44(s,6H).

[0508] Example 81

[0509] 4-(2-Hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0510] Referring to the synthesis method of Example 58, the target product 4-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 81 was synthesized. MS m / z (ESI): 514.2 [M+H] + .

[0511] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),7.91(d,1H),7.85(s,1H),7.50(d,1H), 7.42-7.35(m,1H),7.17-7.11(m,1H),7.02(d,1H),6.89(d,1H),6.52(d,1H), 6.46(d,1H),6.38-6.33(m,1H),5.15(s,1H),4.39-4.27(m,1H),4.27-4.15( m,1H),2.21-2.10(m,2H),2.04-1.84(m,2H),1.66-1.44(m,2H),1.38(s,6H).

[0512] Example 82

[0513] 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)isoindolin-1-one

[0514] Referring to the synthesis method of Reference Example 3, 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)isoindolin-1-one 82 was synthesized. MS m / z (ESI): 508.2 [M+H] + .

[0515] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.32(d,1H),7.90–7.82(m,2H),7.57–7.42(m,3H),7.14(dd,1H),7.01(d,1H),6.61( d,1H),6.54(d,1H),4.85(s,2H),4.38–4.15(m,2H),2.42(s,3H),2.22–2.11(m,2H),2.01–1.91(m,2H),1.66–1.44(m,2H).

[0516] Example 83

[0517] 6-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one

[0518] Referring to the synthesis method of Reference Example 3, 6-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one 83 was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0519] Example 84

[0520] 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridine-3-yl

[0521] 1-Hydroxyisoindolin-1-one

[0522] Referring to the synthesis method of Reference Example 3, 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one 84 was synthesized. MS m / z (ESI): 494.2 [M+H] + .

[0523] Example 85

[0524] 5-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one

[0525] Referring to the synthesis method of Reference Example 3, 5-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one 85 was synthesized. MS m / z (ESI): 508.2 [M+H] + .

[0526] Example 86

[0527] 5-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one

[0528] Referring to the synthesis method of Reference Example 3, 5-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one 86 was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0529] Example 88

[0530] 7-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0531] Referring to the synthesis method of Reference Example 3, 7-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 88 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0532] Example 89

[0533] 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)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0534] Referring to the synthesis method of Reference Example 3, 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)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 89 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0535] 1H NMR(400MHz,DMSO-d6)δ8.82(d,2H),8.31(d,1H),7.83(dd,2H),7.55(s,1H),7.14(dd,1H),7.02(d,1H),6.66(d,1H) ,6.54(d,1H),4.94(s,2H),4.38–4.15(m,2H),2.61(s,3H),2.22–2.11(m,2H),2.01–1.85(m,2H),1.63–1.47(m,2H).

[0536] Example 90

[0537] 6-Methyl-1-carbonyl-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]pyridine-4-carbonitrile

[0538] Referring to the synthesis method of Reference Example 3, 6-methyl-1-carbonyl-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]pyridine-4-carbonitrile 90 was synthesized. MS m / z (ESI): 534.2 [M+H] + .

[0539] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.40(d,1H),7.97(s,1H),7.90–7.82(m,2H),7.18–7.11(m,1H),7.02(d,1H),6.77(d,1H),6.5 6(d,1H),5.19(s,2H),4.37–4.27(m,1H),4.26–4.14(m,1H),2.67(s,3H),2.23–2.09(m,2H),2.05–1.82(m,3H),1.67–1.42(m,2H).

[0540] Example 91

[0541] 2-Methyl-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

[0542] Referring to the synthesis method of Reference Example 3, 2-methyl-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 91 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0543] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.34(d,1H),7.98(d,1H),7.87(dd,1H),7.85(s,1H),7.48(d,1H),7.15(d,1H),7.03(d,1H),6.68(d, 1H),6.56(d,1H),4.87(s,2H),4.33-4.28(m,1H),4.23-4.18(m,1H), 2.60(s,3H),2.19-2.12(m,2H),2.01-1.89(m,2H),1.61-1.48(m,2H).

[0544] Example 112

[0545] 6-(5-Fluoro-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

[0546] Step 1: Reference Example 3e (150 mg, 0.53 mmol), 2,3-difluoro-5-nitro-pyridine (93 mg, 0.58 mmol), and cesium carbonate (428 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at 80°C for 16 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography (elution system B) to afford (1S,3S)-N1-(3-fluoro-5-nitro-2-pyridyl)-N3-[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine 112a (180 mg) in an 80.5% yield. MS m / z (ESI): 426.1 [M+H] + .

[0547] Step 2: Under a hydrogen atmosphere, 112a (158 mg, 0.37 mmol) and palladium / carbon (40 mg, 0.037 mmol, 10% content) were dissolved in methanol (10 mL) and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated to afford 3-fluoro-N2-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridine-2,5-diamine 112b (131 mg) in an 88.5% yield. MS m / z (ESI): 396.1 [M+H] + .

[0548] Step 3: Dissolve 112b (131 mg, 0.33 mmol), methyl 3-(bromomethyl)pyridine-2-carboxylate (85 mg, 0.28 mmol), and N,N-diisopropylethylamine (107 mg, 0.83 mmol) in a mixture of n-butanol (6 mL) and N,N-dimethylformamide (0.5 mL). Stir at 40°C for 11 hours, then at 110°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 112 (100.4 mg) in a 70.7% yield. MS m / z (ESI): 513.2 [M+H] + .

[0549] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.76(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.85(s,1H),7.63(dd,1H),7.14 (dd,1H),7.01(d,1H),6.66(d,1H),4.96(s,2H),4.59–4.15(m,2H),2.24–2.10(m,2H),2.04–1.93(m,2H),1.68–1.51(m,2H).

[0550] Example 114

[0551] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridine-3-yl

[0552] yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2

[0553] Example 12 (30 mg, 0.061 mmol) was dissolved in tetrahydrofuran (2 mL) and deuterated water (1 mL). A 40% deuterated sodium oxide solution (62 mg, 0.607 mmol) was added. The mixture was heated to 35°C and stirred under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried, filtered, and concentrated. The residue was purified by C18 chromatography (elution system C) to give 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 114 (8.7 mg) in a yield of 28.9%.

[0554] MS m / z(ESI):497.1[M+H] + .

[0555] 1 H NMR(400MHz,DMSO-d6)δ8.83-8.79(m,2H),8.37(d,1H),8.14(d,1H),7.90-7.84(m,2H),7.56(dd,1H),7.15(d,1H),7.03(d,1 H),6.68(d,1H),6.55(d,1H),4.33-4.28(m,1H),4.23-4.18(m,1H),2.20-2.13(m,2H),2.00-1.89(m,2H),1.60-1.50(m,2H).

[0556] Example 164

[0557] 6-(5-Fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0558] Step 1: Under nitrogen protection, Reference Example 2c (150 mg, 0.6 mmol), 2,3-difluoro-5-nitropyridine (123 mg, 0.7 mmol) and N,N-diisopropylethylamine (233 mg, 1.8 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 25°C for 16 hours. The reaction was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to obtain (1S,3S)-N 1-(3-Fluoro-5-nitropyridin-2-yl)-N 3 -(7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 164a (200 mg), yield: 87%. MS m / z (ESI): 376.2 [M+H] + .

[0559] Step 2: Under hydrogen atmosphere, 164a (200 mg, 0.5 mmol) and palladium carbon (70 mg, content: 10%) were dissolved in methanol (5 mL), and the reaction was heated to 50 °C and stirred for 2 hours. The reaction was filtered and the filtrate was concentrated to give 3-fluoro-N 2 -((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 164b (170 mg), yield: 97%. MS m / z (ESI): 346.2 [M+H] + .

[0560] Step 3: Under nitrogen, 164b (90 mg, 0.25 mmol) and N,N-diisopropylethylamine (130 mg, 1 mmol) were dissolved in a mixture of N,N-dimethylformamide (2 mL) and tert-butanol (5 mL). Methyl 3-(bromomethyl)picolinate (50 mg, 0.23 mmol) was added with stirring. The reaction was stirred at 25°C for 16 h, then heated to 85°C and stirred for 16 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to give 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 164 (20 mg) in a 17% yield. MS m / z (ESI): 463.2 [M+H] + .

[0561] 1 H NMR(400MHz,DMSO-d6)δ8.76(dd,1H),8.65(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.63(dd,1H),7.27(dd,1H),6.86 (td,1H),6.74(d,1H),6.67(d,1H),4.96(s,2H),4.49(q,1H),4.16(q,1H),2.20–2.10(m,2H),1.98(dt,2H),1.63–1.52(m,2H).

[0562] Example 186

[0563] 5'-Fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0564] Step 1: Dissolve Intermediate Reference Example 2c (60 mg, 0.26 mmol), 5-bromo-2,3-difluoropyridine (99 mg, 0.51 mmol) and N,N-diisopropylethylamine (132 mg, 1.02 mmol) in dimethyl sulfoxide (2 mL). Heat the reaction to 100°C and stir for 16 hours. Add saturated sodium chloride solution to the reaction solution, extract the aqueous phase with ethyl acetate (20 mL x 2), combine the organic phases, dry, and concentrate. The residue is separated by silica gel column chromatography to obtain (1S,3S)-N 1 -(5-bromo-3-fluoropyridin-2-yl)-N 3 -(7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 186a (75 mg), yield: 71.86%. MS m / z (ESI): 409.1 [M+H] + .

[0565] Step 2: Under nitrogen protection, 186a (75 mg, 0.18 mmol), 2-pyridone (52 mg, 0.55 mmol), cuprous iodide (35 mg, 0.18 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.18 mmol) and cesium carbonate (119 mg, 0.37 mmol) were dissolved in 1,4-dioxane (1.5 mL). The reaction was heated to 120 °C and stirred for 16 h. Saturated ammonium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC (formic acid system) to give 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 186 (27.9 mg) in a yield of 35.95%. MS m / z (ESI): 424.2 [M+H]. + .

[0566] 1H NMR(400MHz,DMSO-d6)δ8.71-8.61(m,1H),7.84(d,1H),7.68-7.62(m,1H),7.58-7.53 (m,1H),7.52-7.46(m,1H),7.30-7.24(m,1H),6.94(d,1H),6.90-6.82(m,1H),6.75(d, 1H),6.46(d,1H),6.32-6.25(m,1H),4.62-4.42(m,1H),4.24-4.09(m,1H),2.22-2.07(m,2H),2.05-1.88(m,2H),1.69-1.48(m,2H).

[0567] Example 418

[0568] 6'-(((1S,3S)-3-((6-(3-hydroxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0569] Example 418 can also be prepared according to the following method:

[0570] Step 1: Dissolve 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine 418a (500 mg, 1.87 mmol) in tetrahydrofuran (15 mL) at room temperature. Add sodium borohydride (141.7 mg, 3.75 mmol) with stirring, followed by isopropanol (0.5 mL) and stir for 1 hour. The reaction mixture was filtered, concentrated, and dissolved in dichloromethane (20 mL). Then, 2,3-dichloro-5,6-dicyanobenzoquinone (637.9 mg, 2.81 mmol) was added and the reaction was stirred at room temperature for 1 hour. Dichloromethane (30 mL) was added to the reaction solution, and the organic phase was washed with water (10 mL × 3) and saturated sodium chloride solution (10 mL), dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give 6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine 418b (320 mg) in a yield of 73.5%. MS m / z (ESI): 232.0 [M+H] + .

[0571] Step 2: 418b (170 mg, 0.731 mmol), intermediate 2 (200 mg, 0.731 mmol), and potassium carbonate (202 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction was heated to 100°C and stirred for 3 hours. The reaction mixture was filtered, and the residue was separated by silica gel column chromatography (eluent system B) to give 6'-(((1S,3S)-3-((6-bromopyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 418c (300 mg) in 88.0% yield. MS m / z (ESI): 466.1 [M+H] + .

[0572] Step 3: Under nitrogen protection, 418c (100 mg, 0.214 mmol), 3-hydroxyazetidine hydrochloride (117.5 mg, 1.07 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (34.1 mg, 0.043 mmol) and cesium carbonate (698.7 mg, 2.14 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 100 °C with stirring for 16 h. The reaction mixture was filtered and purified by preparative HPLC (ammonium bicarbonate system) to afford the desired product, 6'-(((1S,3S)-3-((6-(3-hydroxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 418 (15 mg), in a 15.3% yield. MS m / z (ESI): 459.2 [M+H]. + .

[0573] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.18(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.55(d,1H),4.51(m,1H),4.31(m,1H),4.15(m,1H),3. 98(t,2H),3.42(t,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.46(m,2H).

[0574] Example 422

[0575] 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0576] Referring to the synthesis method of Example 418, 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 422 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0577] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.19(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.45(d,1H),4.30(q,1H),4.15(q,1H),3.66(d,2H),3. 52(d,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.45(m,2H),1.24(s,3H).

[0578] The synthesis method of the embodiment can refer to the above embodiment.

[0579] The nuclear magnetic resonance characterization data of the relevant examples are shown in the following table:

[0580] Biological test evaluation

[0581] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0582] Experimental instruments and reagents:

[0583] 1. Instrument:

[0584] Envision (PE-Cisbio: 2105-0020); incubator (Boxun, BC-J80S); centrifuge (Eppendorf: 5810R, Centrifuge 5720R); ice machine (Xueke Electric, IMS-150); water purifier (THERMO: Pacific TⅡ + Micropure); Envision (PE-Cisbio: 2105-0020); plate washer (Thermo: WELLWASH VERSA); microplate shaker (Thermo: 88882006); refrigerator (BCD-268TN, Haier); biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); ultra-clean workbench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.); 5 mL pipette (Research Plus, Eppendorf); 1 mL pipette (Research Plus, Eppendorf); Plus, Eppendorf); constant temperature water bath (HWS-12, Shanghai Yiheng Science); electronic balance (BSA2202S-CW, CPA2202S, Sartorius); ultrasonic cleaner (115F0032, Shanghai Kedao); magnetic stirrer (08-2G, Chijiu); automatic blood biochemistry analyzer (Hitachi 7180, HITACHI).

[0585] 2. Reagents:

[0586] PCSK9-His (Sino Biology, 29698-H08H); Anti-His Tb (Revvity, 61HISTLF); Probe compound (Alexa Fluor 647 labeled, synthesized by Hansoh); DMSO (Sigma, D2650); HEPES buffer pH 7.5 (Beyotime, C0217); Sodium chloride solution (Beyotime, ST347); Calcium chloride solution (Beyotime, ST365); TWEEN 20 (Sigma, P9416); 10% BSA (Thermo, 37525); 384-well plate (Revvity, 6007299); compound dilution plate (Biofil, VWP033096); 50 mL sample trough (Corning, 4870); 50 mL centrifuge tube (Corning, 430829); 2.5 uL pipette (Eppendorf, I36630F); 10 uL pipette (Eppendorf, J13131F); 100 uL pipette (Eppendorf, R22267J); 1000 uL pipette (Eppendorf, I44804F); 10 uL 12-channel electronic pipette (METTLER TOLEDO, 17013797); 300 uL 12-channel electronic pipette (Eppendorf, O51743J); CircuLex Human PCSK9 ELISA kit (MBL: CY-8079); DMEM (Gibco: 31966-021); FBS (Sigma: S5394); Compound plate (Thermo: 1353506); Complete medium: DMEM + 10% FBS + 1X P / S; Experimental medium: DMEM + 10% FBS; Cell line: HepG2 (ATCC: HB-8065); Human LDL R Quantikine ELISA Kit (R&D: DLDLR0); PBS; cell lysis buffer (Thermo: 78503); protease inhibitors (Pierce: 78430); Alamethicin (Abcam); 7-Hydroxycoumarin (Sigma); liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bidex Pharmaceuticals Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck); high-fat diet (Western Diet, D12079B); physiological saline (MA0083-D, meilunbio); Solutol HS15 (102483882, Sigma).

[0587] 1. Combined Experiment

[0588] Test Example 1: Determination of the ability of the compounds of the present invention to bind to PCSK9 protein

[0589] 1. Experimental purpose: To detect the effect of compounds on PCSK9 protein binding using HTRF method.

[0590] 2. Experimental methods:

[0591] 1) Prepare 1x assay buffer consisting of 20 mM HEPES, 150 mM NaCl, 1 mM CaCl2, 0.01% Tween 20, and 0.01% BSA.

[0592] 2) Prepare a 2.5x final concentration of PCSK9-His working solution (30 nM) in 1x assay buffer. Add 8 μL of protein solution to each well of a 384-well plate, except for the Low control well. Add 8 μL of 1x assay buffer to the Low control well.

[0593] 3) Prepare compound working solution: First, dilute the compound from the stock solution uniformly with DMSO (300 μM top, 3-fold, 10 doses). Then, pipette 3.33 μL of the diluted compound into 96.7 μL of 1x assay buffer and mix thoroughly to obtain the prepared compound working solution (10x).

[0594] 4) Pipette 2 μL of compound into the corresponding wells and incubate at 25°C for 10 minutes;

[0595] 5) Prepare a 4x final concentration of the probe compound working solution (90 nM) in 1x assay buffer, mix thoroughly, add 5 μL to each well, and incubate at 25°C for 10 minutes.

[0596] 6) Prepare 4x final concentration of Anti-His Tb working solution (4x) in 1x assay buffer, add 5 μL to each well, and incubate at 25°C for 2 hours.

[0597] 7) Envision Reading HTRF665 / 615 program.

[0598] 3. Experimental data processing method: XLfit four-parameter log (inhibitor) vs. response--Variable slope (four parameters) is used to calculate the compound concentration and the corresponding inhibition rate and nonlinear fitting to calculate IC 50 .

[0599] 4. Experimental results:

[0600] 5. Experimental conclusion: From the data in the table, it can be seen that the example compounds shown in the present invention have a significant binding effect on PCSK-9 protein.

[0601] 2. Cell Function Experiment

[0602] Test Example 1: Determination of the Effect of the Compounds of the Invention on the Concentration of PCSK9 Secreted by HepG2 Cells

[0603] 1. Experimental purpose: To detect the inhibitory effect of compounds on PCSK9.

[0604] 2. Experimental methods:

[0605] 1) HepG2 cells were cultured in complete medium at 37°C, 5% CO2 until they reached 70% to 90% confluency.

[0606] 2) The digested cells were resuspended in experimental culture medium, and 25,000 cells / well / 200 μL were seeded into a 96-well cell culture plate, and cultured at 37° C., 5% CO 2 for 20-24 hours.

[0607] 3) Remove the culture medium from the cell culture plate and add 200 μl of experimental culture medium to each well to wash once.

[0608] 4) Prepare the positive control compound and the test compound: dilute the positive control compound and the test compound on a compound plate.

[0609] 5) Add 250 μL of the diluted compound to each well of the cell culture plate and incubate at 37° C., 5% CO 2 for 48 hours.

[0610] 6) Collect 200 μL of cell culture medium from each well and freeze at -80°C for later use.

[0611] 7) Take out the cell culture medium sample from -80°C, dissolve it, vortex it, centrifuge it, and set aside.

[0612] 8) Prepare the standard curve: Add the corresponding volume of Dilution buffer to each standard tube in sequence. Dilute the standard sample from the original tube or the previous concentration tube in the order of 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, and 0 ng / mL.

[0613] 9) Prepare wash buffer: Dilute 10x wash buffer to 1x with Milli-Q and set aside.

[0614] 10) Add 100 μL of the corresponding standard and culture medium sample to each well, following the designated wells on the plate map. Repeat in duplicate. Apply self-adhesive coverslips, place on a plate shaker at room temperature, gently shake to mix, and incubate for 1 hour.

[0615] 11) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0616] 12) Add 100 μL of HRP-conjugated detection antibody to each well, apply self-adhesive coverslips, place on a shaker to mix thoroughly, and incubate for 1 hour.

[0617] 13) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0618] 14) Add 100 μL of substrate reagent to each well, protect from light, affix a self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 10-20 minutes.

[0619] 15) Add 100 μL of Stop solution (1N H2SO4) to each well and mix thoroughly.

[0620] 16) Measure the optical density (OD) of each well at 450 nm using a microplate reader within 30 minutes of reaction termination.

[0621] 3. Experimental Data Processing: Based on the OD values ​​read by the microplate reader, subtract the OD value of the standard sample group at zero concentration from the OD values ​​of the standard sample, control group, and sample to determine the actual value for each well. Use GraphPad to plot a standard curve and calculate the sample concentration. If the sample is diluted, multiply the dilution factor to obtain the actual sample concentration. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to different concentrations, plot the IC50 using GraphPad.

[0622] 4. Experimental results:

[0623] 5. Experimental conclusion: From the data in the table, it can be seen that the example compounds shown in the present invention showed a strong inhibitory effect in the experiment on the effect of the concentration of PCSK9 secreted by HepG2 cells.

[0624] Test Example 2: Determination of the Effect of the Compounds of the Invention on LDLR Levels in HepG2 Cells

[0625] 1. Experimental purpose: To detect the effect of compounds on LDLR protein levels.

[0626] 2. Experimental methods:

[0627] 1) HepG2 cells were cultured in complete medium at 37°C, 5% CO2 until they reached 70% to 90% confluency.

[0628] 2) The digested cells were resuspended in experimental culture medium, and 25,000 cells / well / 200 μL were seeded into a 96-well cell culture plate, and cultured at 37° C., 5% CO 2 for 20-24 hours.

[0629] 3) Remove the culture medium from the cell culture plate and add 200 μl of experimental culture medium to each well to wash once.

[0630] 4) Prepare the positive control compound and the test compound: dilute the positive control compound and the test compound on a compound plate.

[0631] 5) Add 250 μL of the diluted compound to each well of the cell culture plate and incubate at 37° C., 5% CO 2 for 48 hours.

[0632] 6) Remove the cell culture medium, wash the cells with PBS, and add 50 μL of cell lysis buffer and protein inhibitors.

[0633] 7) Centrifuge, remove the lysate, and store the sample for future use.

[0634] 8) Prepare the standard curve: Add the corresponding volume of Dilution buffer to each standard tube in turn. Take the corresponding volume of the standard from the original tube or the previous concentration tube and dilute it in sequence.

[0635] 9) Prepare wash buffer: Dilute 10x wash buffer to 1x with Milli-Q and set aside.

[0636] 10) Add 80 μL of the corresponding standard and sample to each well, as assigned to the marker and sample wells on the plate map, in duplicate. The well without the standard serves as the background well. Apply a self-adhesive cover slip, place on a plate shaker at room temperature, gently shake to mix, and incubate for 2 hours.

[0637] 11) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0638] 12) Add 200 μL of Human LDLR conjugate to each well, apply a self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 2 hours.

[0639] 13) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0640] 14) Add 200 μL of substrate solution to each well, protect from light, apply self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 20 minutes.

[0641] 15) Add 50 μL of Stop solution to each well and mix thoroughly for 20 minutes.

[0642] 16) Measure the optical density (OD) of each well in sequence at a wavelength of 450 nm using a microplate reader.

[0643] 3. Data Processing: Calculate the actual value for each well by subtracting the OD value of the standard sample group (0 concentration) from the OD values ​​of the standard sample, control group, and sample. Use GraphPad to plot a standard curve and calculate the sample concentration. If the sample is diluted, multiply the dilution factor to obtain the actual sample concentration. Percentage increase in concentration (%) = (actual control concentration - actual sample concentration) / actual control concentration * 100.

[0644] 4. Experimental results:

[0645] 5. Experimental conclusion: From the data in the table, it can be seen that the example compounds of the present invention significantly increased the LDLR concentration in the experiment on the effect on the LDLR concentration of HepG2 cells.

[0646] 3. Pharmacokinetics Experiment

[0647] Test Example 1: Pharmacokinetics in mice

[0648] 1. Experimental purpose: C57BL / 6J mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral and intravenous administration.

[0649] 2. Experimental Plan

[0650] 2.1 Test drug: Compound of the present invention, homemade;

[0651] 2.2 Experimental animals: C57 male mice were purchased from Shanghai Bikai Laboratory Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0652] 2.3 Drug preparation: Oral administration drug preparation: 10% Solutol HS15

[0653] Weigh 10g of Solutol HS15 solid and dissolve it in 90mL of purified water. Mix thoroughly, stir, and sonicate to form a clear solution. Weigh the compound of the present invention and dissolve it in this solution. Shake well and sonicate for 15 minutes to obtain a colorless, clear solution at a concentration of 0.5mg / mL. Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh the compound of the present invention and first add 5% DMSO based on the total volume of the drug to be administered. Vortex and sonicate for 2 minutes to completely dissolve it. Then add 10% Solutol HS15 and vortex and sonicate for 2 minutes to completely dissolve it. Finally, add 85% PBS, vortex and sonicate for 5 minutes. Pass through a 0.22μm filter to obtain a colorless, transparent, clear solution at a concentration of 0.2mg / mL.

[0654] 2.4 Administration: Three male C57 mice were fasted overnight and administered PO at a dose of 5 mg / kg in a 10 mL / kg volume. Three male C57 mice were fasted overnight and administered IV at a dose of 1 mg / kg in a 5 mL / kg volume.

[0655] 2.5 Sample collection: Before administration 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 eye sockets of mice. The blood was placed in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma, which was then stored at -80°C. The mice were fed 4 hours after administration.

[0656] 2.6 Determination results: The final determination results were obtained using the LCMS / MS method.

[0657] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0658] 4. Experimental conclusions:

[0659] The results of the pharmacokinetic assay in C57BL / 6J mice showed that the compound of the present invention exhibited a good PK advantage. Test Example 2: Pharmacokinetic assay in cynomolgus monkeys

[0660] 1. Study purpose: To study the pharmacokinetic behavior of the compound of the present invention in cynomolgus monkeys (plasma) at a dose of 5 mg / kg orally administered to cynomolgus monkeys as test animals.

[0661] 2. Experimental plan:

[0662] 2.1 Experimental drugs: Compounds of the present invention, homemade.

[0663] 2.2 Experimental animals: 3 male cynomolgus monkeys per group, from Xiongsen, Guangxi, animal production license number: SCXK(Gui)2021-0004).

[0664] 2.3 Preparation Prescription: Oral administration drug preparation: 10% Solutol HS15 in water

[0665] Weigh 10g of solid Solutol HS15 into 90ml of ddH2O in a 100ml volumetric flask. Vortex, mix, and sonicate to obtain a clear solution. Weigh the compound into a 100ml glass vial, add this solution, and vortex and sonicate for 10 minutes to obtain a white suspension at a concentration of 1mg / mL.

[0666] 2.4 Administration: Three male cynomolgus monkeys were fasted overnight and administered orally at a dose of 5 mg / kg in a volume of 5 mL / kg.

[0667] 2.5 Sample Collection: Blood Collection: 0.3 mL of blood was collected from the forelimb vein of cynomolgus monkeys before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood was placed in EDTA-K2 anticoagulant tubes, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at -80°C. The monkeys were fed 4 h after administration.

[0668] 2.6 Sample processing:

[0669] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed, and centrifuged at 3500×g for 5-20 minutes.

[0670] 2) The supernatant solution after treatment was subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument was AB Sciex API 4000 Qtrap.

[0671] Liquid phase analysis: Liquid phase conditions: Shimadzu LC-20AD pump

[0672] ●Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile Flow rate: 0.4mL / min

[0673] Elution time: 0-4.0 minutes, eluent is as follows:

[0674] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0675] 4. Experimental conclusion: The pharmacokinetic test results of cynomolgus monkeys showed that the compound of the present invention showed a good PK advantage, among which the compound AUC 0-∞ (ng / mL×h) is 20000~50000, and the AUC of the dominant compound is 0-∞ (ng / mL×h) is 30,000 to 50,000.

[0676] Test Example 3: In vitro metabolic stability study of the compounds of the present invention in mouse, rat and human liver microsomes

[0677] 1. Experimental purpose: The purpose of this study is to evaluate the metabolic stability of the compound in phase I and partially phase II in mouse, rat and human liver microsomes.

[0678] 2. Experimental Plan

[0679] 2.1 Drug preparation: The compounds of the present invention were prepared into 10 mM stock solutions with DMSO (or other suitable solutions) and stored at -20°C until use. The compounds of the present invention were prepared in-house.

[0680] 2.2 Experimental steps

[0681] 1) Prepare buffer solution: Dissolve 4.01 mL of 1 M K2HPO4·3H2O (AR grade) and 0.99 mL of 1 M KH2PO4 (AR grade) in ultrapure water and dilute to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0682] 2) Prepare compound working solution: Prepare compound working solution by adding 2 μL of compound stock solution to 998 μL of phosphate buffer for a final concentration of 20 μM. Adjust the ratio and final concentration appropriately based on the properties of the compound.

[0683] 3) Prepare liver microsome working solution: dilute 156.3 μL of 20 mg / mL microsomes to 5 mL with 100 mM phosphate buffer and mix thoroughly to a final concentration of 0.625 mg / mL.

[0684] 4) Prepare NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA and add 2 mL of 100 mM phosphate buffer to a final concentration of 20 mM.

[0685] 5) Prepare the pore-forming agent (Alamethicin): Weigh 1 mg of Alamethicin and add it to 200 μL of methanol to make a 5 mg / mL solution. Remove 10 μL of this solution and add it to 990 μL of phosphate buffer (pH 7.4) for a final concentration of 50 μg / mL.

[0686] 6) Prepare the reaction stop solution: dilute the internal standard with acetonitrile (or other suitable solution) to make the stop solution and store it in a refrigerator at 2-8°C.

[0687] 7) Incubation Procedure: 400 μL of prepared liver microsomes, 25 μL of compound working solution (20 μM), and 25 μL of alamethicin (50 μg / mL) were added sequentially to a 96-well plate and pre-incubated at 37°C for 10 min. The reaction was then initiated by adding 50 μL of prepared NADPH / UDPGA and incubated at 37°C. The total reaction volume was 500 μL, and the final concentrations of the components were as follows:

[0688] 50 μL was taken out at the time points of 0, 5, 15, 30, 60 and 120 min, and 200 μL of cold stop solution containing internal standard was added to terminate the sample reaction. The sample was centrifuged at 3500 rpm for 10 min, and the supernatant was taken for LC-MS / MS analysis.

[0689] 2.4 Chromatographic analysis

[0690] 1) Chromatographic conditions:

[0691] Instrument: Shimadzu LC-20AD; Column: Phenomenex C18 (50*4.6mm, 5μm particle size); mobile phase: A: 0.1% formic acid in water, B: acetonitrile; flushing gradient: 0.2-1.6min 5% A to 95% A, 3.0-3.1min 95% A to 5% A; flow rate: 1.0ml / min; run time: 4.0min; injection volume: 5μL.

[0692] 2) Mass spectrometry conditions

[0693] Instrument: API4000 liquid chromatography-mass spectrometer, AB Sciex; ion source: electrospray ionization (ESI); drying gas: N2, temperature: 500°C; electrospray voltage: 5000 V; detection mode: positive ion detection; scanning mode: molecular reaction monitoring (MRM); scanning time: 0.8401 s.

[0694] 3. Data processing: Calculate the original data according to the following formula:

[0695] Residual rate % = peak area ratio of compound to internal standard at any time point / peak area ratio of compound to internal standard at 0 minutes × 100

[0696] T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0697] In vitro liver microsomal intrinsic clearance (CL) was calculated by Ke int ) and hepatic intrinsic clearance (CL int,liver )

[0698] CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation mg / mL)

[0699] CL int,liver =CL int × amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0700] Based on the well-stirred model, the in vivo hepatic clearance (CL int,liver )

[0701] CL=(CL int,liver ×fu×Qh) / (CL int,liver ×fu+Qh), where fu represents the free fraction in the blood, which defaults to 1. The parameters in the formula are shown in the table below.

[0702] 4. Experimental results:

[0703] 5. Experimental conclusion: The results show that the advantageous embodiment compounds of the present invention exhibit stable metabolic effects in various liver microsomes, especially in human liver microsomes.

[0704] IV. Drug Efficacy Experiment

[0705] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse hyperlipidemia animal model

[0706] 1. Experimental purpose: To evaluate the in vivo efficacy of the compound in the B6-hPCSK9 transgenic mouse hyperlipidemia animal model.

[0707] 2 Experimental operation and data processing

[0708] 2.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[0709] 2.2 Animal Model: After arriving at the barrier system, animals were acclimated for 1 week and then fed a high-fat diet. Animal weight and food intake were recorded weekly.

[0710] 2.3 Grouping and Dosing

[0711] a. Grouping was done by random grouping.

[0712] c. According to the grouping results, the test drug was administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once a day or single administration; administration cycle: 21 days; solvent: 10% Solutol HS15 / 90% Saline). Test drug: compound of the present invention, homemade.

[0713] d. After the start of the test drug administration, the animals were weighed and fed twice a week, and blood was collected once a week.

[0714] e. Data were processed using Excel or other software. Body weight change (BWC) (%) = (weight at the end of treatment - weight at the start of treatment) / weight at the start of treatment × 100%; food intake (g / mice / day) = (previous feed addition + previous feed remainder - current feed remainder) / number of animals / number of feeding days; Calculation of blood biochemical inhibition rate: Using the blood biochemical results of the vehicle group tested in the same batch as the baseline, the data of each treatment group were normalized, and the percentages of TC and LDL-C were calculated according to the following formulas: TC percentage change (%) = (post-dose TC value - pre-dose TC value) / pre-dose TC value × 100%; LDL-C percentage change (%) = (post-dose LDL-C value - pre-dose LDL-C value) / pre-dose LDL-C value × 100%. Plasma PCSK9 was detected by ELISA.

[0715] 3 Experimental results:

[0716] 4. Experimental conclusion: The example compounds shown in the present invention can effectively lower LDL-C in the B6-hPCSK9 transgenic mouse hyperlipidemia animal model.

Claims

1. A compound represented by the general formula (IA), or a stereoisomer or pharmaceutically acceptable salt thereof: , Where ring A is selected from , , , , , , or ; ring B is selected from , , , , , , , , , , , , , , , , , , , , , or ; R a selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, oxo, thio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R c-1 selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R c-2selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R c-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R d selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, oxo, thio, C 1-6deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl or 5-12-membered heteroaryl; alternatively, any two adjacent or non-adjacent R d connected to form C 3-8 cycloalkyl or 3-8 membered heterocyclyl; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; e is equal to 0, 1, 2, or 3.

2. A compound or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound is further represented by the general formula (IA-1): .

3. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further represented by the general formula (I-1-a): , Where each of R a-1-R a-4 independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl.

4. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is further represented by the general formula (I-1-a'): .

5. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is selected from , , , , , , or .

6. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein R a selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3-CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, .

7. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein R b selected from -H or -F; and / or R d selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2- CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH or .

8. A compound or its stereoisomer or pharmaceutically acceptable salt according to claim 1, where R c-1 selected from –F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, or ; and / or where R c-2 selected from –H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, or -O-CH(CH3)2; and / or where R c-3selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2 or .

9. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 3, where each of R a-1 -R a-4 independently selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3, or .

10. A compound represented by the general formula (IA), or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the following compounds: or .

11. A compound represented by the general formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof: , Where X2 is amino, nitro, halogen, boronic acid, or boronate; each of the other groups is as defined in paragraph 1.

12. A compound represented by the general formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound is selected from the following compounds: or .

13. A method for producing a compound represented by the general formula (IA) according to claim 1, wherein the method comprises the following step: , Where X3 is hydroxyl, amino, methylthio, halogen, boronic acid, or boronate; allowing a compound represented by general formula (IV) to react with a compound represented by general formula (IV-1) to obtain a compound represented by general formula (IA); and each of the other groups is as defined in paragraph 1.

14. A pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (IA) or its stereoisomer or pharmaceutically acceptable salt according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. The pharmaceutical composition according to claim 14, wherein the weight percentage of the compound or its stereoisomer or pharmaceutically acceptable salt in the composition is 0.1-95%.

16. The pharmaceutical composition according to claim 14, wherein the weight percentage of the compound or its stereoisomer or pharmaceutically acceptable salt in the composition is 0.5-85%.

17. The pharmaceutical composition according to claim 14, wherein the weight percentage of the compound or its stereoisomer or pharmaceutically acceptable salt in the composition is 1-60%.

18. The pharmaceutical composition according to claim 14, wherein the weight percentage of the compound or its stereoisomer or pharmaceutically acceptable salt in the composition is 10-50%.

19. The pharmaceutical composition according to claim 14, wherein the weight percentage of the compound or its stereoisomer or pharmaceutically acceptable salt in the composition is 15-40%.

20. A pharmaceutical composition according to any one of claims 15-19, wherein the compound is additionally represented by the general formula (IA): , Where ring A is selected from , , , , , or ; ring B is selected from , , , , , , , , , , , , , , , , , , , , , or ; R a selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 alkyl; R c-1 selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R c-2 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R c-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen-C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; R d selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, oxo, thio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl or C 5-12 heteroaryl; alternatively, any two adjacent or non-adjacent R d connected to form C 3-8 cycloalkyl or 3-8 membered heterocyclyl; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; e is equal to 0, 1, 2, or 3.

21. The pharmaceutical composition according to claim 20, wherein the compound is additionally represented by the general formula (IA-1): .

22. The pharmaceutical composition according to claim 20, wherein the compound is additionally represented by the general formula (I-1-a): , where each of R a-1 -R a-4 independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl.

23. The pharmaceutical composition according to claim 20, wherein the compound is additionally represented by the general formula (I-1-a'): .

24. The pharmaceutical composition according to claim 20, wherein ring B is selected from , , , , , , or .

25. The pharmaceutical composition according to claim 22, where each of R a-1 -R a-4 independently selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3, or .

26. The pharmaceutical composition according to claim 20, where R b selected from -H or -F.

27. The pharmaceutical composition according to claim 20, where R c-2 selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, or -O-CH(CH3)2; and / or where R c-3 selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2 or .

28. The pharmaceutical composition according to claim 20, where R dselected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2- CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH or .

29. The pharmaceutical composition according to claim 20, wherein the compound is selected from the following compounds: or .

30. The use of a compound represented by general formula (IA) or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 20 for inhibiting PCSK9 in a subject in need thereof.

31. The use of a compound represented by the general formula (IA) or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 20 for reducing LDL levels in a subject in need thereof.

32. The use of a compound represented by the general formula (IA) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 20 for the treatment of a cardiovascular disease, cerebrovascular disease, atherosclerosis and / or a disease associated therewith or a symptom thereof.

33. The use according to claim 32, wherein the cardiovascular disease, cerebrovascular disease, atherosclerosis is selected from stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal change in lipoprotein levels, atherosclerosis, liver steatosis, metabolic syndrome and / or coronary artery disease.

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