Nitrogen-containing heterocyclic derivative inhibitors, methods for producing the same, and applications

Abstract

This invention relates to nitrogen-containing heterocyclic derivative inhibitors, methods for producing the same, and applications thereof. In particular, this invention relates to compounds represented by general formula (I), methods for producing the same, pharmaceutical compositions containing the compound, and their use as inhibitors in the treatment of cardiovascular diseases, cerebrovascular diseases, and other diseases, where each substituent in general formula (I) is as defined in the specification.

Description

[Technical Field]

[0001] This application is a Chinese patent application with filing date July 4, 2023, application number 202310818758.5, application date August 10, 2023, application number 202311011109.0, application date September 21, 2023, application number 202311227801.7, application date November 17, 2023, application date It claims priority rights to China Patent Application No. 202410052828.5, filed on January 12, 2024; China Patent Application No. 202410173281.4, filed on February 6, 2024; China Patent Application No. 202410407937.4, filed on April 3, 2024; and China Patent Application No. 202410426055.2, filed on April 9, 2024.

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

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

[0004] PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease that is highly expressed in the liver. PCSK9 gene loss-of-function mutations are associated with low LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), and have been clinically validated as a target for the treatment of hyperlipidemia. PCSK9 is synthesized as an enzyme precursor, undergoes autocatalytic cleavage within the cell after synthesis, and propeptide-bond-matured PCSK9 is secreted extracellularly, where the propeptide bond blocks the catalytic activity of PCSK9.

[0005] PCSK9 is a major modulator of hepatocyte surface low-density lipoprotein receptor (LDLR) levels and can inhibit the LDLR circulation pathway. LDLR function is crucial for maintaining cholesterol homeostasis and is responsible for the uptake and degradation of low-density lipoproteins. Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100, and the LDL / LDLR complex is internalized by receptor-mediated endocytosis. The intracellular low pH environment releases LDL from LDLR, which then circulates back to the cell membrane. The free intracellular LDL is then delivered to lysosomes for degradation. Secreted PCSK9 participates in LDLR circulation by binding to hepatocyte surface LDLR. After the PCSK9 / LDLR complex migrates through a treoprotein-encapsulated indentation into the acidic endosomal compartment, conformational changes in LDLR lead to the formation of further binding sites with PCSK9. Therefore, PCSK9 upregulates LDL-C levels by disrupting LDLR circulation, accompanied by LDLR degradation into lysosomes.

[0006] Familial hypercholesterolemia (FH) is a genetic disorder of low-density lipoprotein cholesterol metabolism, affecting approximately 1 in 250 people. It is characterized by significantly elevated LDL-C levels. Heterozygous FH patients have a 3-4 times higher risk of developing coronary heart disease (CAD) compared to healthy individuals, and CAD often develops an average of 10 years earlier. Statins reduce low-density lipoprotein cholesterol in heterozygous FH patients, and studies by Beselin suggest that high-intensity statin therapy can reduce the risk and mortality of coronary heart disease by 44%. However, in many cases, the reduction in LDL-C is considered insufficient. The inverse compensation mechanism of statins involves upregulating sterol regulatory element-binding protein 2 (SREBP-2), thereby activating the LDL receptor and PCSK9, increasing PCSK9 expression and secretory binding to LDLR, and resulting in elevated blood LDL-C levels. Therefore, while statins reduce LDL by inhibiting HMG-CoA, they exert an anti-balancing effect on the action of SREPB, and adding PCSK9 inhibitors to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatment routes such as PCSK9 inhibitors are necessary.

[0007] Alirocumab and Evolocumab, monoclonal antibody-based PCSK9 macromolecule inhibitors, are FDA-approved drugs with good safety profiles for selectively binding to extracellular PCSK9, blocking its interaction with LDLR, and lowering LDL-C levels. Studies have shown that in heterozygous FH patients who have not achieved their LDL-C targets after statin monotherapy, a single injection of Alirocumab every two weeks can significantly reduce cardiovascular risk. Alirocumab also shows a moderate increase in "good" cholesterol (HDL-C). Furthermore, the PCSK9 siRNA drug Inclisiran is currently available and has good safety profiles for long-term lipid reduction by decreasing PCSK9 protein expression levels. However, both of the above drugs must be administered by injection and have high production costs, resulting in high prices. As no PCSK9 small molecule inhibitors are currently available, there is a high demand for orally administered PCSK9 small molecule inhibitors.

[0008] PCSK9 small molecule inhibitors have been reported in patents such as International Publication No. 2014 / 170786 (Pfizer), International Publication No. 2014 / 150326 (Shifa), International Publication No. 2020 / 150473 (AZ), and International Publication No. 2022 / 133529 (Nyrada). Currently, the most advanced is AZD-0780, which is in Phase I clinical trials, while the others are all in preclinical development. Several polypeptides have also been reported, the most advanced of which is in Phase II clinical trials. The present invention necessitates the development of an orally administered PCSK9 small molecule inhibitor. [Overview of the Initiative] [Means for solving the problem]

[0009] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] Here, ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, L1 is 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) nNR cc C(O)R dd -,-(CH2) n S(O) m NR aa R bb -and-(CH2) n NR cc S(O) m R dd - Selected from, R aa , R bb、 R cc and R dd Each of these groups is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent substituents may bond to form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group may be optionally further substituted. Preferably, L1 is selected from a bond, -C(O)- or -C(O)NH-, R a This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 selected from, and the amino group, alkyl group, alkenyl group, alkynyl group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, R A1 ~R A3Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Preferably, R a These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Aryl group, 5-14 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 RA3 ,-(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 Selected from the above, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 Selected from an aryl group or a 5-14 membered heteroaryl group, the amino group, C 1-6Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. Alternatively, any two adjacent or non-adjacent R a These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R b This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R B1 ,-(CH2) n UreB1 ,-(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, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R B1 ~R B3Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Preferably, R b These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Aryl group, 5-14 member heteroaryl group, -(CH2) n R B1 ,-(CH2) n Ure 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 RB3 ,-(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 Selected from the above, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R B1 ~RB3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 Selected from an aryl group or a 5-14 membered heteroaryl group, the amino group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. Alternatively, any two adjacent or non-adjacent R b These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Preferably, or any two R a and R b These groups bond to form a heterocyclyl group or a heteroaryl group, and the heterocyclyl group and heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, or C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. R c This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R C1 ~R C3 Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Preferably, R c These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Aryl group, 5-14 member heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R C1 ~R C3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14Selected from an aryl group or a 5-14 membered heteroaryl group, the amino group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. Alternatively, any two adjacent or non-adjacent R c These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R d This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) nR D1 ,-(CH2) n Ure 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, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R D1 ~R D3Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Preferably, R d These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Aryl group, 5-14 member heteroaryl group, -(CH2) n R D1 ,-(CH2) n Ure D1 ,-(CH2) n C(O)R D1 ,-(CH2) n C(O)OR D1 ,-(CH2) n S(O) m R D1 ,-(CH2) n NR D2 R D3 ,-(CH2) n NR D2 C(O)OR D3 ,-(CH2) n NR D2 C(O)(CH2) n1 RD3 ,-(CH2) n NR D2 C(O)NR D2 R D3 ,-(CH2) n C(O)NR D2 (CH2) n1 R D3 , -OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 Selected from the above, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R D1 ~R D3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 Selected from an aryl group or a 5-14 membered heteroaryl group, the amino group, C 1-6Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. Alternatively, any two adjacent or non-adjacent R d These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two R c and R d These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. x is 0, 1, 2, or 3, y is 0, 1, 2, or 3, and z is 0, 1, 2, or 3. e is 0, 1, 2, or 3, m is 0, 1, or 2, and n is 0, 1, 2, 3, or 4. n1 is 0, 1, 2, 3 or 4, and n2 is 0, 1, 2, 3 or 4. n3 is 0, 1, 2, 3 or 4, and n4 is 0, 1, 2, 3 or 4.

[0010] In a preferred embodiment of the present invention, the compound is further represented by the general formula (IA), [ka] Here, ring A is C 3-8 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, preferably selected from a 5-membered nitrogen-containing heteroaryl group, a 5-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl group, a 5-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl group, a 6-membered nitrogen-containing heteroaryl group, a 6-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl group, or a 6-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl group. Ring B is C 3-8 Cycloalkyl group, 5-12 member heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, preferably C 3-6 Selected from cycloalkyl groups, phenyl groups, 5-membered nitrogen-containing heterocyclyl groups, 6-membered nitrogen-containing heterocyclyl groups, 5-membered nitrogen-containing heteroaryl groups, 6-membered nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heterocyclyl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heterocyclyl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heterocyclyl groups, or 6-membered condensed 6-membered bicyclic nitrogen-containing cycloaryl groups. R c-1 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3Alkylthio group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be optionally further substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. R C1 ~R C3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group, preferably R c-1 -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, Or, R c-1 Preferably, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl group, C 1-3Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C1-3 An alkoxy group, C 1-3 A hydroxyalkyl group, a C substituted with a cyano group 1-3 An alkyl group, C 3-8 A cycloalkyl group, a 3- to 8-member heterocyclyl group, C 6-10 The aryl group and the 5- to 12-member heteroaryl group may optionally be further substituted, and optionally with deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 An alkyl group, C 1-3 A deuterated alkyl group, C 1-3 A haloalkyl group, C 1-3 A hydroxyalkyl group, C 1-3 An alkoxy group, C 1-3 A deuterated alkoxy group, C 1-3 A haloalkoxy group, C 2-4 An alkenyl group, C 2-4 An alkynyl group, C 3-8 A cycloalkyl group, a 3- to 8-member heterocyclyl group, C 6-10 May be further substituted with one or more substituents of the aryl group and the 5- to 12-member heteroaryl group, R C1 ~R C3 Each independently is hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 An alkyl group, C 1-3 A deuterated alkyl group, C 1-3 A haloalkyl group, C 1-3 A hydroxyalkyl group, C 1-3 An alkoxy group, C 1-3 A deuterated alkoxy group, C 1-3 A haloalkoxy group, C 2-4 An alkenyl group, C 2-4 An alkynyl group, C 3-8 A cycloalkyl group, a 3- to 8-member heterocyclyl group, C 6-10 Selected from an aryl group or a 5- to 12-member heteroaryl group, the amino group, C 1-3 An alkyl group, C 1-3 A deuterated alkyl group, C 1-3 A haloalkyl group, C 1-3Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R c-1 -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, More preferably, R c-1 It is selected from -F, R c-2 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3A C substituted with a hydroxyalkyl group and a cyano group 1-3 alkyl group, C 3-8 cycloalkyl group, 3- to 8-membered heterocyclyl group, C 6-10 aryl group, 5- to 12-membered heteroaryl group, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 selected from, the amino group, C 1-3 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-3 alkylthio group, C 1-3 deuterated alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, halo C 1-3 alkoxy group, C 1-3 A C substituted with a hydroxyalkyl group and a cyano group 1-3Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. R C1 ~R C3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R c-2 -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, R c-3 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10Aryl group, 5-12 member heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. R C1 ~R C3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R c-3 -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, Comfortable, R c-3 -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, m is 0, 1, or 2, n is 0, 1, 2, 3, or 4, and n1 is 0, 1, 2, 3, or 4. The definitions of the other elements are as described above.

[0011] In a preferred embodiment of the present invention, the compound is further represented by the general formula (IA-1), [ka] The definition of the base is as described above.

[0012] In a more preferred embodiment of the present invention, ring A described in the present invention is selected from a 5-membered monoheteroaryl group, a 5-membered condensed 5-membered bicyclic heteroaryl group, a 5-membered condensed 6-membered bicyclic heteroaryl group, a 6-membered monoheteroaryl group, a 6-membered condensed 5-membered bicyclic heteroaryl group, or a 6-membered condensed 6-membered bicyclic heteroaryl group. More preferably, [ka] Selected from.

[0013] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-2'), [ka] L1 is selected from the bonds, -C(O)-, -C(O)NH-, -C(O)NCH3-, or -C(O)N(CH3)2, and M5 is selected from N or CR5. R5 consists of hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Selected from aryl groups and 5-14 membered heteroaryl groups, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The group may be further substituted with one or more substituents from among aryl groups and 5- to 10-membered heteroaryl groups, and the definitions of the other groups are as described above.

[0014] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1-a), [ka] Here, R a-1 ~R a-4 These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, oxo group, thio group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C1-6 C substituted with hydroxyalkyl groups and cyano groups 1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 Aryl group, 5-14 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkylthio group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkoxy group, C 1-6 C substituted with hydroxyalkyl groups and cyano groups1-6 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-12 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 Selected from an aryl group or a 5-14 membered heteroaryl group, the amino group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The aryl group and the 5-14 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 They may be further substituted with one or more substituents from an aryl group and a 5-14 membered heteroaryl group. The definitions of other elements are as described above. m is 0, 1, or 2, n is 0, 1, 2, 3, or 4, and n1 is 0, 1, 2, 3, or 4.

[0015] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1-a'), [ka] The definition of the base is as described above.

[0016] In a more preferred embodiment of the present invention, ring B described in the present invention is C 3-6 Selected from cycloalkyl groups, phenyl groups, 3-8 membered heterocyclyl groups, 7-10 membered bicyclic heterocyclyl groups, 5 membered heteroaryl groups, 6 membered heteroaryl groups, 5 membered condensed 5 membered bicyclic heteroaryl groups, 5 membered condensed 6 membered bicyclic heteroaryl groups, 6 membered condensed 5 membered bicyclic heteroaryl groups, or 6 membered condensed 6 membered bicyclic heteroaryl groups. More preferably, ring B is C 3-6 Selected from cycloalkyl groups, phenyl groups, 5-membered nitrogen-containing heterocyclyl groups, 6-membered nitrogen-containing heterocyclyl groups, 7-10-membered bicyclic heterocyclyl groups, 5-membered nitrogen-containing heteroaryl groups, 6-membered nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, or 6-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups. More preferably, ring B is pyridine, pyrimidine, benzene, [ka] Selected from, More preferably, ring B is selected from pyridine, pyrimidine, pyridone, or pyrimidone. More preferably, ring B is pyridine, pyrimidine, benzene, [ka] Selected from.

[0017] In a more preferred embodiment of the present invention, R described in the present invention a These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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) nC(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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R a is -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, [ka] Selected from, More preferably, R ais -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, [ka] Selected from, More preferably, R a is -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, [ka] Selected from.

[0018] In a more preferred embodiment of the present invention, R described in the present invention a-1 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R A1 ,-(CH2)n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R a-1 is -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, [ka] Selected from, More preferably, R a-1 is -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, [ka] Selected from.

[0019] In a more preferred embodiment of the present invention, R described in the present invention a-2 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R a-2 is -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, [ka] Selected from, More preferably, R a-2 is -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, [ka] Selected from.

[0020] In a more preferred embodiment of the present invention, R described in the present invention a-3 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R a-3 is -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, [ka] Selected from, More preferably, R a-3 is -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, [ka] Selected from.

[0021] In a more preferred embodiment of the present invention, R described in the present invention a-4 These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R A1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R A1 ~R A3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R a-4 is -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, [ka] Selected from, More preferably, R a-4 is -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, [ka] Selected from.

[0022] In a more preferred embodiment of the present invention, R described in the present invention b These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R B1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. R B1 ~R B3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R b The -H or -F option is selected.

[0023] In a more preferred embodiment of the present invention, any two R as described in the present invention b It is bonded to an adjacent atom C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 It forms an aryl group or a 5-12 membered heteroaryl group.

[0024] In a more preferred embodiment of the present invention, R described in the present invention a and R b These groups bond to form a 5-12 membered heterocyclyl group or a 5-12 membered heteroaryl group, and the 5-12 membered heterocyclyl group or 5-12 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, or C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Haloalkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 The group may be further substituted with one or more substituents from an aryl group and a 5- to 14-membered heteroaryl group.

[0025] In a more preferred embodiment of the present invention, R described in the present invention c These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R C1 ,-(CH2) n Ure 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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. RC1 ~R C3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R c -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from, Comfortable, R c -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, [ka] Selected from.

[0026] In a more preferred embodiment of the present invention, R described in the present invention d These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, oxo group, thio group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Aryl group, 5-12 member heteroaryl group, -(CH2) n R D1 ,-(CH2) n Ure D1 ,-(CH2) n C(O)R D1 ,-(CH2) n C(O)OR D1 ,-(CH2) n S(O) m R D1 ,-(CH2) n NR D2 RD3 ,-(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 Selected from the above, the amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylthio group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 C substituted with hydroxyalkyl groups and cyano groups 1-3 Alkyl alkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The amino group, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, Halo C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-10 membered heteroaryl group can optionally be deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-10 membered heteroaryl group. R D1 ~R D3 These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Selected from an aryl group or a 5-12 membered heteroaryl group, the amino group, C 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. 1-3 Alkyl alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Haloalkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 They may be further substituted with one or more substituents from an aryl group and a 5-12 membered heteroaryl group. Preferably, R d -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, [ka] Selected from, More preferably, Rd -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, [ka] Selected from, More preferably, R d -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, [ka] Selected from.

[0027] In a more preferred embodiment of the present invention, the compound [ka] Preferably, [ka] Selected from.

[0028] In a more preferred embodiment of the present invention, the compound [ka] teeth, [ka] Selected from, where R c-1 , R c-2 and R c-3 The definition is R c It is the same as, preferably, R c-1 , R c-2 and R c-3 The definition is as follows:c-1 , R c-2 and R c-3 This is as defined.

[0029] The present invention further provides a compound represented by general formula (IV), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] Here, X2 is an amino group, a nitro group, a halogen, a boric acid, or a boric acid ester, and the other groups are as described above. Preferably, the compound represented by the general formula (IV) is as shown in (IV-A), (IV-B), or (IV-C). [ka]

[0030] In a more preferred embodiment of the present invention, a compound of general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] It is characterized by being selected from the following compounds.

[0031] The present invention further provides a method for compounding the compound represented by general formula (IA), which comprises the following steps: [ka] Here, X3 is a hydroxyl group, an amino group, a halogen, a boric acid, or a boric acid ester. General formula compound (IV) and general formula compound (IV-1) are reacted to obtain general formula compound (IA). The other units are as described above. Preferably, the compound represented by the general formula (IA) is as shown in (IA-1), (I-1-a), or (I-1-a'). [ka]

[0032] The present invention further relates to a pharmaceutical composition comprising any compound of general formula (I) shown in a therapeutically effective amount, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0033] The present invention further relates to the application of any of the general formula (I) compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the manufacture of PCSK9 inhibitor drugs.

[0034] The present invention further relates to the application of any of the general formula (I) compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, in the manufacture of LDL-reducing drugs, wherein the LDL is LDL-C.

[0035] The present invention further relates to the application of compounds represented by general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the manufacture of drugs for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or symptoms thereof, and more preferably, in the manufacture of drugs for stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal lipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0036] The present invention relates to a method for producing compounds represented by general formula (I), their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for the treatment of cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or symptoms thereof, and more preferably to applications in the production of products for the treatment of stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal lipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0037] The present invention further relates to methods for preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal lipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, which comprises administering to a patient a therapeutically effective amount of a compound described in the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] Furthermore, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15% to 40%, even more preferably 20% to 30%, and even more preferably 20% to 25%, based on the total weight of the pharmaceutical composition.

[0039] The present invention further provides a method for treating a disease state using the compound or pharmaceutical composition of the present invention, the disease state including, but not limited to, conditions related to PCSK9.

[0040] The present invention further relates to a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal lipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in mammals, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof to the mammal. [Modes for carrying out the invention]

[0041] Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0042] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched 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 group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, and 5-methylhexyl group. Examples include 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, the lower alkyl group contains 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups, and in the present invention, preferably methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, haloalkyl groups, deuterated alkyl groups, alkyl groups substituted with alkoxy groups, and alkyl groups substituted with hydroxyl groups.

[0043] The term "alkylene group" refers to a group in which one hydrogen atom of an alkyl group is further substituted. For example, a "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylene group" refers to -(CH2)3-, and a "butylene group" refers to -(CH2)4-. The term "alkenyl group" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Examples include vinyl groups, 1-propenyl groups, 2-propenyl groups, and 1-, 2-, or 3-butenyl groups. The alkenyl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0044] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, where the ring of a cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include spirocyclic, fused, and crosslinked cyclic cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl groups.

[0045] The term "spirocycloalkyl group" refers to a 5-20 membered polycyclic group in which monocyclic rings share one carbon atom (called a spiro atom), and which may contain one or more double bonds, but does not have any rings with a fully conjugated π-electron system. Preferably, it is 6-14 membered, and more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] This includes, This also includes spirocycloalkyl groups in which monospirocycloalkyl groups and heterocycloalkyl groups share a spiro atom, and non-limiting examples include: [ka] This includes, among others.

[0046] The term "condensed cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, where one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it is 6-14 member, more preferably 7-10 member. Depending on the number of constituent rings, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl group, preferably bicyclic or tricyclic, more preferably a 5-member / 5-member or 5-member / 6-member bicyclic cycloalkyl group. Non-limiting examples of condensed cycloalkyl groups are: [ka] This includes, among others.

[0047] A "crosslinked cycloalkyl group" refers to a 5-20 membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds, but which do not have any rings with a fully conjugated π-electron system. Preferably, it has 6-14 members, and more preferably, 7-10 members. Depending on the number of rings, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups include the following: [ka]

[0048] The cycloalkyl ring can be condensed onto an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring linked to the basic skeleton is a cycloalkyl group, and non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0049] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, where one or more ring atoms are nitrogen, oxygen, or S(O). mA heteroatom selected from (where m is an integer between 0 and 2), but without the ring portion of -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, the heterocyclyl group is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered group containing 3 to 12 ring atoms, where 1 to 4 are heteroatoms, more preferably containing 3 to 8 ring atoms, most preferably containing 3 to 8 ring atoms, and even more preferably containing 1 to 3 nitrogen atoms. The heterocyclyl group is optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, and contains nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing condensed heterocyclyl groups. Alternatively, it is a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heterocyclyl group containing 5 to 12 ring atoms, where 1 to 4 are heteroatoms, and even more preferably containing 1 to 3 nitrogen and / or oxygen atoms.

[0050] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, azepanyl group, 1,4-diazacycloheptyl group, and pyranyl group, with pyrrolidinyl group, morpholinyl group, piperidinyl group, azepanyl group, 1,4-diazacycloheptyl group, and piperazinyl group being preferred. Polycyclic heterocyclyl groups include spiro rings, fused rings, and bridging ring heterocyclyl groups, where such spiro rings, fused rings, and bridging ring heterocyclyl groups are optionally linked to other groups via single bonds, or further linked in parallel to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups via any two or more atoms on the ring.

[0051] The term "spiroheterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which monocyclic rings share one atom (called a spiro atom), where one or more ring atoms are nitrogen, oxygen, or S(O). mA heteroatom selected from (where m is an integer from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but there are no rings having a fully conjugated π-electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of covalent spiroatoms between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] This includes, among others.

[0052] The term "condensed heterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, where one or more ring atoms are nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) is a heteroatom selected from the above, and the other ring atoms are carbon. Preferably, it has 6 to 14 members, and more preferably, 7 to 10 members. Depending on the number of rings that make up the group, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl group, preferably bicyclic or tricyclic, and more preferably a 5-membered fused 5-member or 5-membered fused 6-member bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] This includes, among others.

[0053] The term "bridged heterocyclyl group" refers to a 5-14 member polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds, but which have no rings having a fully conjugated π-electron system, where one or more ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer from 0 to 2), and the other ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings it comprises, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyl group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging heterocyclyl groups are: [ka] This includes, among others.

[0054] The heterocyclyl ring may be condensed onto an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring linked to the basic skeleton is a heterocyclyl group, and non-limiting examples include: [ka] This includes, among others.

[0055] The heterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0056] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-12 membered, such as a phenyl group and a naphthyl group. More preferably, a phenyl group. The aryl group ring may be fused onto a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, and includes a benzo 5-10 membered heteroaryl group, a benzo 3-8 membered cycloalkyl group, and a benzo 3-8 membered heteroalkyl group, preferably a benzo 5-6 membered heteroaryl group, a benzo 3-6 membered cycloalkyl group, and a benzo 3-6 membered heteroalkyl group, where the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, an oxygen atom, and a sulfur atom, or further includes a three-membered nitrogen-containing fused ring containing a benzene ring.

[0057] Here, the ring connected to the basic framework is an aryl ring, and a non-restrictive example of this is: [ka] This includes, among others.

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

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

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

[0061] The heteroaryl ring may be condensed onto an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring linked to the basic skeleton is a heteroaryl ring, and non-limiting examples include: [ka] This includes, among others.

[0062] The heteroaryl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, oxo groups, or carboxylate groups.

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

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

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

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

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

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

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

[0070] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0071] Various phrases 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, indicating that X can be one or more of A, B, or C.

[0072] The enol structure and lactam structure in the compound described in the present invention are tautomers, and those skilled in the art will see that they are the same molecule, for example. [ka] It should be understood that these are the same molecule.

[0073] Any of the hydrogen atoms described in the present invention may be substituted with its isotope deuterium, and any of the hydrogen atoms in the compounds of the examples according to the present invention may also be substituted with a deuterium atom.

[0074] "Optional" or "optionally" means that the event or environment described later may occur but is not required, and the description includes cases where the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclyl group" means that an alkyl group may be present but is not required, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0075] "Substituting" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are substituted independently of each other by a corresponding number of substituents. Needless to say, substituents exist only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable if bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

[0076] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0077] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in the body of a mammal and possesses the desired biological activity.

[0078] The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

[0079] Examples The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) was given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterium hydroxide (D2O) as the measurement solvent, and the internal standard (if any) was tetramethylsilane (TMS).

[0080] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 A 150 x 4.6 mm chromatography column is used.

[0081] Thin-layer chromatography (TLC) silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254. TLC plates were 0.15 mm to 0.20 mm in size, while thin-layer chromatography plates were 0.4 mm to 0.5 mm in size for product separation and purification. Column chromatography generally used Yantai Huanghai silica gel with a particle size of 200 to 300 mesh as the support.

[0082] The compounds of the present invention have significant advantages in terms of drug-forming properties such as solubility, permeability, and safety.

[0083] The starting materials used in the embodiments of this invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0084] Unless otherwise specified, all reactions of the present invention were carried out under a dry nitrogen gas or argon gas atmosphere with continuous magnetic stirring, using a dry solvent, and the reaction temperature was in degrees Celsius.

[0085] The eluent systems used for silica gel column chromatography and the developing solvent systems for thin-layer chromatography in the purification of intermediates and 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 compound, and can also be adjusted by adding small amounts of alkaline or acidic reagents such as triethylamine and acetic acid.

[0086] Unless otherwise specified, in the embodiments of the present invention, the ratio of the mobile phase under HPLC chiral restructuring conditions to HPLC chiral analysis conditions was a volume ratio.

[0087] Intermediate 1 (1S,3S)-N1-(5-(difluoromethoxy)pyrimidine-2-yl)cyclopentan-1,3-diamine [ka] Intermediate 1 was synthesized by referring to the manufacturing method described in International Publication No. 2020 / 150473. MS m / z (ESI): 245.1[M+H] + .

[0088] Intermediate 1 can also be obtained by the following method. [ka]

[0089] Step 1: 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) were dissolved in dimethyl sulfoxide (10 mL), and the reaction was heated to 100 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature, added to water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, sequentially washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified and separated by silica gel chromatography (elution system B) to obtain (1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentylcarboxylate tert-butyl 1B (2.1 g). The yield was 55.1%. MS m / z (ESI): 345.2[M+H] + .

[0090] Step 2: Dissolve 1B (2.1 g, 6.1 mmol) in methanol (10 mL), add a 4 M dioxane hydrochloride solution (20 mL), and stir the reaction at room temperature for 2 hours. Concentrate the reaction mixture, add ammonia methanol solution (7 M, 10 mL) to adjust the pH to weakly alkaline, concentrate again, and then purify the residue by silica gel chromatography (elution system A) and separate to obtain (1S,3S)-N 1 Intermediate 1 (1.3 g) of -(5-(difluoromethoxy)pyrimidine-2-yl)cyclopentan-1,3-diamine was obtained, with a yield of 87.3%. MS m / z (ESI): 245.1[M+H] + .

[0091] Intermediate 2 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0092] Step 1: 2-Fluoro-5-iodopyridine 2A (5g, 22.4 mmol), 2-hydroxypyridine (2.35g, 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 (9.5g, 29.2 mmol) were dissolved in 1,4-dioxane (75 mL). The reaction was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, added to 100 mL of water, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, sequentially washed with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to obtain 6'-fluoro-2H-[1,3'-bipyridine]-2-one 2B (3.1 g), with a yield of 72.7%. MS m / z (ESI): 191.1[M+H] + .

[0093] Step 2: Tert-butyl(1S,3S)-3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridine]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were dissolved in dimethyl sulfoxide (30 mL), and the reaction was heated to 130 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, added to water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, sequentially washed with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to obtain tert-butyl((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl) carbamate 2C (2.9 g), with a yield of 78.4%. MS m / z (ESI): 371.2[M+H] + .

[0094] Step 3: Dissolve tert-butyl((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g, 7.83 mmol) in 4 M dioxane hydrochloride solution (30 mL) and stir the reaction at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography column (eluent system C) to obtain 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one intermediate 2 (1.5 g), with a yield of 70.9%. MS m / z (ESI): 271.2 [M+H] + .

[0095] Reference Example 1 6'-((3-(((1S,3S)-7-fluoro-[1,2,4]triazazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0096] Step 1: Dissolve 7-fluoro-[1,2,4]triazazolo[1,5-a]pyridine-2-amine Reference Example 1a (100 mg, 0.657 mmol) in acetonitrile under ice bath, 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, raise the temperature to room temperature, continue stirring, and detect completion of the reaction using a thin-layer chromatography plate. Add saturated sodium bicarbonate solution dropwise to the reaction mixture until the pH reaches 7. Extract the reaction mixture with dichloromethane (10 mL x 3), dry the organic phase, concentrate it, and separate the residue by silica gel column chromatography (eluent system A) to obtain 2-chloro-7-fluoro-[1,2,4]triazazolo[1,5-a]pyridine Reference Example 1b (65 mg) with a yield of 77.5%. MS m / z (ESI): 172.1[M+H] + .

[0097] Step 2: Under nitrogen gas protection, 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 mixture was heated to 130°C and reacted under microwaves for 2 hours. The reaction mixture was heated to 130°C under nitrogen gas protection and reacted for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (alkaline system) to obtain 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one Reference Example 1 (6.6 mg), with a yield of 4.08%. MS m / z (ESI): 406.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.69-6.59(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).

[0098] Reference Example 2 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0099] Step 1: Under nitrogen gas protection, 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-bisdiphenylphosphino-9,9-dimethylxanthene (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL), heated to 130 °C by microwave, 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 obtain tert-butyl N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino]cyclopentyl]carbamate Reference Example 2b (240 mg), with a yield of 30.9%. MS m / z (ESI): 336.0[M+H] + .

[0100] Step 2: Reference Example 2b (202 mg, 0.60 mmol) was dissolved in methanol (2 mL) at room temperature and stirred. A solution of 1,4-dioxane hydrochloride (4 M, 5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (aqueous ammonia system) to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine Reference Example 2c (140 mg), with a yield of 98.6%. MS m / z (ESI): 236.2[M+H] + .

[0101] Step 3: Reference Example 2c (150 mg, 0.64 mmol), 2-fluoro-5-nitropyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL), and the reaction 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]pyridine-2-yl)-N3-(5-nitropyridine-2-yl)cyclopentan-1,3-diamine Reference Example 2d (190 mg), with a yield of 83.4%. MS m / z (ESI): 358.1[M+H] + .

[0102] Step 4: Under a hydrogen gas atmosphere, at room temperature, Reference Example 2d (190 mg, 0.53 mmol) and palladium carbon (28 mg, 0.026 mmol, content: 10%) were dissolved in methanol (5 mL) and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain N2-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)pyridine-2,5-diamine Reference Example 2e (170 mg), with a yield of 97.7%. MS m / z (ESI): 328.1[M+H] + .

[0103] Step 5: At room temperature, Reference Example 2e (80 mg, 0.24 mmol), methyl 3-(bromomethyl)pyridinecarboxylate (62 mg, 0.27 mmol), and potassium carbonate (101.2 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 mL), stirred for 1 hour, and then the temperature was raised 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 obtain 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one Reference Example 2 (24.3 mg), with a yield of 22.4%. MS m / z (ESI): 445.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.75(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).

[0104] Reference Example 3 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0105] Following the synthesis method of Reference Example 2, the compound 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one was synthesized to obtain Reference Example 3. MS m / z (ESI): 495.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.83(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).

[0106] Reference Example 3 can also be manufactured by referring to the method described below. [ka]

[0107] Step 1: Dissolve 4-(trifluoromethyl)pyridine-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-pyridyl]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] + .

[0108] Step 2: At room temperature, 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) were dissolved in methanol (100 mL), stirred for 20 minutes, then heated to 65°C and stirred for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain Reference Example 3b (5.0 g) with a yield of 80.60%. MS m / z (ESI): 203.1 [M+H] + .

[0109] Step 3: Reference Example 3b (5 g, 24.74 mmol) and copper bromide (5.52 g, 24.74 mmol) were dissolved in acetonitrile (50 mL), and tert-butyl nitrite (12.75 g, 123.68 mmol) was added. The reaction was stirred at room temperature for 0.5 hours, then the temperature was raised to 70°C and stirred for 2 hours. The reaction mixture was concentrated, the residue was diluted with ethyl acetate (150 mL), filtered, the organic phase was washed with water (100 mL), concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine Reference Example 3c (5 g), with a yield of 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0110] Step 4: Under nitrogen gas protection, 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-bisdiphenylphosphin-9,9-dimethylxanthene (2.94 g, 5.07 mmol) were dissolved in 1'4-dioxane (120 mL). The reaction 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 obtain tert-butyl N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]amino]cyclopentyl]carbamate reference example 3d (3.7g), with a yield of 56.76%. MS m / z (ESI): 386.2[M+H] + .

[0111] Step 5: At room temperature, Reference Example 3d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) were dissolved in methanol (10 mL) and stirred for 1 hour. The reaction mixture was concentrated, the residue was diluted with methanol, and the pH was adjusted to 8-10 with saturated sodium bicarbonate solution. After concentration, the residue was purified by silica gel column chromatography (elution system A) to obtain (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine Reference Example 3e (2.74 g), with a yield of 100%. MS m / z (ESI): 286.2 [M+H] + .

[0112] Step 6: Reference Example 3e (2.74 g, 9.61 mmol), 2-fluoro-5-nitropyridine (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-nitropyridine-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine Reference Example 3f (3.8 g), with a yield of 97.12%. MS m / z (ESI): 408.1[M+H] + .

[0113] Step 7: Under a hydrogen gas atmosphere, Reference Example 3f (3.8 g, 9.33 mmol) and palladium carbon (993 mg, 0.93 mmol, purity: 10%) were dissolved in methanol (60 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated to obtain N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)pyridine-2,5-diamine Reference Example 3 g (3.2 g), which was used directly in the next step without purification. MS m / z (ESI): 378.1 [M+H] +

[0114] Step 8: Reference example 3 g (2.0 g, 5.30 mmol), methyl 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 4.24 mmol), and N,N-diisopropylethylamine (2.05 g, 15.90 mmol) were dissolved in a mixed solvent of tert-butanol (20 mL) and N,N-dimethylformamide (4 mL), stirred at room temperature for 1 hour, then heated to 40°C and stirred for 16 hours, and further heated to 80°C and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to obtain 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (Reference Example 3) (1.2g), with a yield of 45.79%. MS m / z (ESI): 495.2[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0115] Reference Example 4 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazine-2-one [ka]

[0116] Step 1: Under nitrogen gas protection, 2-fluoro-5-iodopyridine reference example 4a (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazine-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 allowed to return to room temperature, saturated sodium chloride solution (120 mL) was added, the aqueous phase was extracted with ethyl acetate (40 mL x 3), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 1-(6-fluoropyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazine-2-one Reference Example 4b (1.4 g, pale yellow solid). The yield was 57.87%. MS m / z (ESI): 246.1[M+H] + .

[0117] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazine-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 the reaction was heated to 130 °C and stirred for 48 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was separated by reverse-phase HPLC (ammonium bicarbonate system) to obtain 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazine-2-one (Reference Example 4, 41 mg, white solid), with a yield of 30.47%. MS m / z (ESI): 470.1[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(m,2H),7.26-6.82(m,1H),6.97(d,1H) ,6.59(d,1H),4.42-4.19(m,2H),3.40(s,3H),2.22-2.05(m,2H),1.95-1.82(m,2H),1.61-1.42(m,2H).

[0118] Reference Example 5 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridine-7-one [ka]

[0119] Step 1: Under nitrogen gas protection, 2-fluoro-5-iodopyridine Reference Example 4a (2.2 g, 9.87 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (1.59 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol), and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 hours. The reaction mixture was allowed to return to room temperature, saturated sodium chloride solution (120 mL) was added, the aqueous phase was extracted with ethyl acetate (40 mL x 3), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 6-(6-fluoropyridine-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridine-7-one Reference Example 5b (1.3 g), with a yield of 57.49%. MS m / z (ESI): 230.1[M+H] + .

[0120] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridine-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridine-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). The reaction was heated to 130 °C and stirred for 48 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was separated by reverse-phase HPLC (formic acid system) to obtain 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridine-7-one Reference Example 5 (46 mg), with a yield of 35.4%. MS m / z (ESI): 454.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.76(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).

[0121] Reference Example 6 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0122] Step 1: At 0°C, lithium bistrimethylsilylamide (1M, 3.6mL) was added to a solution of Reference Example 5b (167 mg, 0.73 mmol) and iodomethane (517 mg, 3.64 mmol) in tetrahydrofuran (3 mL). The reaction was heated to room temperature and stirred for 3 hours. At 0°C, saturated ammonium chloride solution was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 6-(6-fluoropyridine-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one Reference Example 6a (110 mg). The yield was 58.69%. MS m / z (ESI): 258.1[M+H] + .

[0123] Step 2: Under nitrogen gas protection, 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), and the reaction was heated to 130 °C and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (15 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one reference example 6 (32.1 mg), with a yield of 24.50%. MS m / z (ESI): 482.3[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.79-8.69(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),7.23-6.8 2(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).

[0124] Example 1 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0125] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 1 was synthesized. MS m / z (ESI): 438.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.73(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(dd,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).

[0126] Example 3 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0127] Example 3 can also be obtained by the following method. [ka]

[0128] Step 1: Under nitrogen gas protection, 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine 3a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine dichloride palladium (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL), and the reaction was heated to 125 °C and stirred for 5 hours. The reaction was allowed to return to room temperature, 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, the aqueous phase was extracted with ethyl acetate (25 mL x 6), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-yl)ethane-1-one 3b (445 mg). The yield was 67.26%. MS m / z (ESI): 177.1[M+H] + .

[0129] 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) to the reaction mixture, 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 with the organic phase, dry, 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, filter to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-yl)ethane-1-one 3c (320 mg), yielding a yield of 51.05%. MS m / z (ESI): 240.0 [M + H] + .

[0130] Step 3: Sodium borohydride (29 mg, 0.76 mmol) was added to a methanol (4 mL) solution of 3c (140 mg, 0.58 mmol) at 0°C, and the mixture was stirred for 1 hour. Saturated ammonium chloride solution was slowly added dropwise to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-yl)ethane-1-ol 3d (136 mg). The yield was 96.33%. MS m / z (ESI): 242.0 [M+H] +

[0131] Step 4: Under nitrogen gas protection, 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), and the reaction was heated to 130 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (15 mL x 2), the organic phase was combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 3 (1 mg), with a yield of 1.10%. MS m / z (ESI): 432.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.49(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,1H),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).

[0132] Example 4 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0133] Following the synthesis method in Reference Example 2, the compound was synthesized to obtain 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 4. MS m / z (ESI): 445.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.80(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).

[0134] Example 5 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0135] Following the synthesis method in Reference Example 2, the compound was synthesized to obtain 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 5. MS m / z (ESI): 441.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.80(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).

[0136] Example 6 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0137] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 6 was synthesized. MS m / z (ESI): 454.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.63(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).

[0138] Example 7 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0139] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 7 was synthesized. MS m / z (ESI): 472.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.74(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,1H),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).

[0140] Example 8 6'-(((1S,3S)-3-((7-(3-hydroxyazetidine-1-yl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0141] Step 1: At room temperature, tert-butyl nitrite (1.45 g, 14.08 mmol) and copper bromide (3.15 g, 14.08 mmol) were dissolved in acetonitrile (50 mL) and stirred. The reaction was heated to 70°C, and 7-bromo-[1,2,4]triazole[1,5-a]pyridine-2-amine 8a (2.0 g, 9.39 mmol) was gradually added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain 2,7-dibromo-[1,2,4]triazole[1,5-a]pyridine 8b (2.5 g) with a yield of 96.2%. MS m / z (ESI): 275.9[M+H] + .

[0142] Step 2: Under nitrogen gas 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 obtain 1-(2-bromo-[1,2,4]triazole[1,5-a]pyridine-7-yl)azetidine-3-hydroxy-8c (100 mg). The yield was 20.6%. MS m / z (ESI): 269.0[M+H] + .

[0143] Step 3: Under nitrogen gas protection, 8c (100 mg, 0.372 mmol), intermediate 2 (100.5 mg, 0.372 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol), 2-biscyclohexylphosphine-2',6'-diisopropoxybiphenyl (35 mg, 0.074 mmol), and cesium carbonate (363 mg, 1.11 mmol) were dissolved in 1,4-dioxane (10 mL), heated to 130 °C, and stirred for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product 6'-(((1S,3S)-3-((7-(3-hydroxyazetidine-1-yl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 8 (10 mg), with a yield of 5.87%. MS m / z (ESI): 459.2[M+H] + . 1 1H NMR (400MHz, DMSO-d6) δ 8.14(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7.41(dd,1H),6.97(d ,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H),6.27(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).

[0144] Example 9 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidine-1-yl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0145] The target product 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidine-1-yl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 9 was synthesized by referring to the synthesis method of Example 8. MS m / z (ESI): 473.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.15(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7.41(dd,1H),6.9 8(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),3.82-3.7 4(m,4H),2.24-2.10(m,2H),1.91(t,2H),1.57-1.48(m,2H),1.41(s,3H).

[0146] Example 11 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0147] Step 1: Under nitrogen gas protection, 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine 11a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine dichloride palladium (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL), and the reaction was heated to 125 °C and stirred for 5 hours. The reaction was allowed to return to room temperature, 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, the aqueous phase was extracted with ethyl acetate (25 mL x 6), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-yl)ethane-1-one 11b (445 mg). The yield was 67.26%. MS m / z (ESI): 177.1[M+H] + .

[0148] Step 2: Dissolve 11b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL), heat to 70°C, and stir. Add tert-butyl nitrite (458 mg, 4.44 mmol) to the reaction mixture and continue stirring 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 with the organic phase, dry, concentrate to remove most of the solvent, add (PE / EA = 1 / 1, 10 mL) to the residue, stir at 0°C for 15 minutes, filter to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-yl)ethane-1-one 11c (320 mg), yielding a yield of 51.05%. MS m / z (ESI): 240.0 [M+H] + .

[0149] Step 3: Methylmagnesium bromide (1M, 0.7mL) was added dropwise to a solution of 11c (80mg, 0.33 mmol) of tetrahydrofuran (2mL) at 0°C. The reaction was heated to room temperature and stirred for 1 hour. Saturated sodium chloride solution was added to the reaction mixture at 0°C. The aqueous phase was extracted with ethyl acetate (15mL x 2). The organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-yl)propan-2-ol 11d (60mg). The yield was 70.30%. MS m / z (ESI): 256.0[M+H] + .

[0150] Step 4: Under nitrogen gas protection, 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 the reaction was heated to 130 °C and stirred for 16 hours. The reaction mixture was allowed to return to room temperature, saturated sodium chloride solution was added, the aqueous phase was extracted with ethyl acetate (15 mL x 2), the organic phase was combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 11 (8.7 mg), with a yield of 10.00%. MS m / z (ESI): 446.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.47(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),6.60-6.49(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).

[0151] Example 12 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0152] Following the synthesis method in Reference Example 2, the compound was synthesized to obtain 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 12. MS m / z (ESI): 495.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.85-8.74(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),6.6 9(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).

[0153] Example 13 2-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazine-3(2H)-one

[0154] Example 13 can also be manufactured by referring to the method described below. [ka]

[0155] Step 1: Under nitrogen gas protection, 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), heated to 130°C, and stirred for 16 hours. The reaction mixture was filtered, the filtrate was diluted with saturated sodium chloride solution, extracted with ethyl acetate (30 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 2-(6-fluoropyridine-3-yl)pyridazin-3(2H)-one 13b (856 mg), with a yield of 49.93%. MS m / z (ESI): 192.0 [M+H] + .

[0156] Step 2: Under nitrogen gas 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-bisdiphenylphosphino-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 obtain tert-butyl((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)carbamate 13d (473 mg), with a yield of 42.91%. MS m / z (ESI): 336.2[M+H] + .

[0157] Step 3: Add hydrochloric acid / 1,4-dioxane solution (4 M, 3.53 mL) to a solution of 13d (473 mg, 1.41 mmol) of dichloromethane (4 mL) and stir at room temperature for 2 hours. The reaction mixture was concentrated, the residue was dissolved in a small amount of dichloromethane and methanol, and 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 obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 13e (310 mg) in yield of 93.43%. MS m / z (ESI): 236.1 [M + H] +

[0158] Step 4: Under nitrogen gas protection, 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 was heated to 130 °C and stirred for 48 hours. The reaction mixture was filtered, and the filtrate was separated by reverse-phase HPLC to obtain 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazine-3(2H)-one 13 (16.8 mg), with a yield of 15.80%. MS m / z (ESI): 407.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.69-8.62(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).

[0159] Example 14 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0160] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 14 was synthesized. MS m / z (ESI): 402.2[M+H] +. 1 H NMR (400MHz,DMSO-d6) δ 8.42(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).

[0161] Example 15 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0162] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 15 was synthesized. MS m / z (ESI): 424.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 9.22(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).

[0163] Example 18 6'-(((1S,3S)-3-((7-Methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0164] Following the synthesis method in Reference Example 1, 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 18 was synthesized. MS m / z (ESI): 418.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.40(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),6.2 6(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).

[0165] Example 19 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one

[0166] Example 19 can also be manufactured by referring to the method described below. [ka]

[0167] Step 1: Under nitrogen gas protection, 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 was heated to 130°C and stirred for 48 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by reverse-phase HPLC to obtain 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 19 (7.3 mg), with a yield of 9.94%. MS m / z (ESI): 473.3[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.80-8.72(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),6.93-6.81(m,2 H),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).

[0168] Example 20 3-Fluoro-6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0169] Following the synthesis method in Reference Example 2, 3-fluoro-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 20 was synthesized. MS m / z (ESI): 463.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.76(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).

[0170] Example 21 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidine-7-one [ka]

[0171] Following the synthesis method in Reference Example 2, the compound was synthesized to obtain 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidine-7-one 21. MS m / z (ESI): 446.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.86-8.79(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).

[0172] Example 22 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidine-7-one [ka]

[0173] Following the synthesis method in Reference Example 3, the compound was synthesized to obtain 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidine-7-one 22. MS m / z (ESI): 496.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 9.41(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).

[0174] Example 23 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2-(2-hydroxypropane-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0175] Following the synthesis method in Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2-(2-hydroxypropane-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 23 was synthesized. MS m / z (ESI): 503.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.70-8.62(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,1 H),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).

[0176] Example 25 2-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-7-(trifluoromethyl)isoindole-1-one [ka]

[0177] Following the synthesis method in Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-7-(trifluoromethyl)isoindole-1-one 25 was synthesized. MS m / z (ESI): 512.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.66(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,1H),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).

[0178] Example 26 2-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-4-(trifluoromethyl)isoindole-1-one [ka]

[0179] Following the synthesis method in Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-4-(trifluoromethyl)isoindole-1-one 26 was synthesized. MS m / z (ESI): 512.1[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.66(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,2 H),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).

[0180] Example 27 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0181] Following the synthesis method in Reference Example 3, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 27 was synthesized. MS m / z (ESI): 513.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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),6.5 6(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).

[0182] Example 28 3-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)pyrimidine-4(3H)-one [ka]

[0183] The target product 3-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)pyrimidine-4(3H)-one 28 can also be synthesized by referring to the synthesis method in Reference Example 1. MS m / z (ESI): 407.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.73-8.58(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).

[0184] Example 29 1-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)pyrazine-2(1H)-one [ka]

[0185] The target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)pyrazine-2(1H)-one 29 can also be synthesized by referring to the synthesis method in Reference Example 1. MS m / z (ESI): 407.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.70-8.61(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,1H),6.90-6. 81(m,1H),6.75(d,1H),6.55(d,1H),4.39-4.26(m,1H),4.22-4.10(m,1H),2.21-2.06(m,2H),2.02-1.80(m,2H),1.64-1.42(m,2H).

[0186] Example 31 6'-(3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridine]-2(1H)-one Example 31 can also be manufactured by referring to the following method. [ka]

[0187] Step 1: Under nitrogen gas protection, (1S,3S)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-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 was heated 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). 1-(5-bromopyridine-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 31a (200 mg) was obtained, with a yield of 60%. MS m / z (ESI): 391.0 [M+H] + .

[0188] Step 2: Under nitrogen gas protection, 31a (170 mg, 0.4 mmol), (2-oxo-1H-pyridine-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)ferrocene dichloride palladium (64 mg, 0.1 mmol) was added, and the reaction was heated to 80°C and stirred for 1 hour. The reaction was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 6'-(3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridine]-2(1H)-one 31 (90 mg), with a yield of 51%. MS m / z (ESI): 406.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 11.66(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).

[0189] Example 32 6'-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridine]-2-one [ka]

[0190] Step 1: Under nitrogen gas protection, Reference Example 2c (100 mg, 0.43 mmol), 2-fluoro-5-iodopyridine (142 mg, 0.64 mmol), and diisopropylethylamine (165 mg, 1.28 mmol) were dissolved in dimethyl sulfoxide (1.8 mL), and the reaction was heated to 130 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain (1S,3S)-N 1 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-N 3 -(5-iodopyridine-2-yl)cyclopentan-1,3-diamine 32a (95 mg) was obtained, with a yield of 51.00%. MS m / z (ESI): 439.0[M+H] + .

[0191] Step 2: Under nitrogen gas protection, 32a (50 mg, 0.11 mmol), 3-(2-hydroxypropan-2-yl)pyridine-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 and stirred for 2 hours. Saturated sodium chloride solution was added to the reaction mixture, extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridine]-2-one 32 (25.1 mg), with a yield of 47.46%. MS m / z (ESI): 464.2[M+H] + . 11H NMR (400MHz, DMSO-d6) δ 8.70-8.62(m,1H),7.91(d,1H),7.65-7.59(m,1H),7.56-7.52(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,1H),4. 22-4.09(m,1H),2.22-2.07(m,2H),2.04-1.81(m,2H),1.64-1.37(m,8H).

[0192] Example 33 6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2-methyl-5,6-dihydro-7H-pyrrole[3,4-d]pyrimidine-7-one [ka]

[0193] Following the synthesis method in Reference Example 2, the target product 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2-methyl-5,6-dihydro-7H-pyrrole[3,4-d]pyrimidine-7-one 33 was synthesized. MS m / z (ESI): 460.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 9.10(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).

[0194] Example 49 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0195] Step 1: Lithium diisopropylamide (2M, 1.05mL) was added dropwise to a solution of 2-bromo-6-tert-butylpyridine 49a (300 mg, 1.40 mmol) in tetrahydrofuran (5 mL) at -78°C. The reaction was stirred at -78°C for 1 hour. Then, N,N-dimethylformamide (410 mg, 5.60 mmol) was added dropwise to the reaction mixture. The reaction was slowly raised to room temperature and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 2-bromo-6-(tert-butyl)nicotinaldehyde 49b (56 mg). The yield was 16.51%. MS m / z (ESI): 242.0[M+H] + .

[0196] Step 2: Under carbon monoxide protection, 49b (53 mg, 0.22 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride palladium (16 mg, 0.02 mmol), and triethylamine (44 mg, 0.44 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (1 mL) and methanol (2 mL). The reaction was heated to 80°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, extracted with ethyl acetate (15 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 6-(tert-butyl)-3-formylpyridinecarboxylate methyl 49c (13 mg). The yield was 26.84%. MS m / z (ESI): 222.1[M+H]+ .

[0197] Step 3: Reference Example 2e (23 mg, 0.07 mmol), 49c (13 mg, 0.06 mmol), and acetic acid (5 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (2 mL), and the reaction was heated to 60°C and stirred for 1 hour. After the reaction mixture returned to room temperature, sodium triacetoxyborohydride (62 mg, 0.29 mmol) was added to the reaction mixture and stirred for 15 hours. Saturated ammonium chloride solution was added to the reaction mixture, extracted with dichloromethane (20 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 49 (15.8 mg), with a yield of 53.72%. MS m / z (ESI): 501.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.70-8.62(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,1 H),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).

[0198] Example 50 2-(6-((1S,3S)-3-((7-Fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino]pyridine-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]pyridine-1-one [ka]

[0199] Following the synthesis method in Reference Example 2, 2-(6-((1S,3S)-3-((7-fluoro-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino]pyridine-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]pyridine-1-one 50 was synthesized. MS m / z (ESI): 461.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 12.03(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).

[0200] Example 51 2-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one [ka]

[0201] Step 1: At room temperature, methyl 5-amino-2-bromopyridine-4-carboxylate (10 g, 43.28 mmol) and N-bromosuccinimide (8.47 g, 47.61 mmol) were dissolved in 1,2-dichloroethane (70 mL) and stirred for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain methyl 3-amino-2,6-dibromopyridine-4-carboxylate 51a (12.5 g) with a yield of 93.18%. MS m / z (ESI): 308.9, 310.9, 312.9 [M+H] + .

[0202] Step 2: Under nitrogen gas protection, 51a (12.4 g, 40.01 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriboloxane in tetrahydrofuran solution (3.5 M, 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 temperature was raised to 100 °C, and the mixture was stirred for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain methyl 3-amino-2,6-dimethylisonicotinate 51b (5 g) with a yield of 69.35%. MS m / z (ESI): 181.1[M+H] + .

[0203] Step 3: At room temperature, 51b (4.8 g, 26.64 mmol) and copper bromide (2.97 g, 13.32 mmol) were dissolved in acetonitrile (80 mL), and tert-butyl nitrite (8.24 g, 79.91 mmol) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 30 minutes, then the temperature was raised to 60°C and stirred 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 obtain methyl 3-bromo-2,6-dimethylisonicotinate 51c (4.9 g) in yield of 75.37%. MS m / z (ESI): 244.0,246.0[M+H] + .

[0204] Step 4: Under nitrogen gas protection, 51c (500 mg, 2.05 mmol), potassium tert-butoxymethyltrifluoroborate (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 mixed solvent of toluene (13 mL) and water (0.5 mL). The reaction was heated to 120 °C and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (40 mL), the organic phase was washed with water, and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain methyl 3-(tert-butoxymethyl)-2,6-dimethylisonicotinate 51d (300 mg). The yield was 58.27%. MS m / z (ESI): 252.0[M+H] + .

[0205] Step 5: At room temperature, 51d (300 mg, 1.19 mmol) was dissolved in dichloromethane (7 mL), and 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, the residue was diluted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium bicarbonate solution, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 4,6-dimethylflu[3,4-c]pyridine-1(3H)-one 51e (120 mg), with a yield of 61.61%. MS m / z (ESI): 164.1[M+H] + .

[0206] Step 6: Under nitrogen gas protection, 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 toluene solution of trimethylaluminum (2 M, 0.43 mL) was added dropwise to the reaction mixture, and the mixture was heated to 90°C and stirred for 1 hour. While stirring, methanol (10 mL) was added dropwise to the reaction mixture, and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution system A) to obtain N-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-3-(hydroxymethyl)-2,6-dimethylisonicotinamide 51f (30 mg), with a yield of 28.6%. MS m / z (ESI): 491.2[M+H] + .

[0207] Step 7: At room temperature, 51f (20 mg, 0.04 mmol) and triphenylphosphine (21.4 mg, 0.08 mmol) were dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarboxylate (16.5 mg, 0.08 mmol) was added. The mixture was stirred for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to obtain 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one 51 (1.2 mg). The yield was 6.23%. MS m / z (ESI): 473.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.69-8.62(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),6.54(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).

[0208] Example 52 1-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)piperidine-2-one [ka]

[0209] The target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)piperidine-2-one 52 was synthesized by referring to the synthesis method of Example 32. MS m / z (ESI): 410.2[M+H]+ . 1 H NMR (400MHz,DMSO-d6) δ 8.70-8.60(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).

[0210] Example 53 4-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)morpholin-3-one [ka]

[0211] The target product 4-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-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] + . 1 H NMR (400MHz,DMSO-d6) δ 8.71-8.61(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).

[0212] Example 54 5-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5-azaspiro[2,4]heptan-4-one [ka]

[0213] The target product 5-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5-azaspiro[2,4]heptan-4-one 54 was synthesized by referring to the synthesis method of Example 32. MS m / z (ESI): 422.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.69-8.61(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).

[0214] Example 55 6-(6-(((1S,3S)-3-((7-Cyclopropyl-[1,2,4]Triazolo[1,5-a]Pyridine-2-yl)amino)cyclopentyl)amino)Pyridine-3-yl)-5,6-Dihydro-7H-Pyrrolo[3,4-b]Pyridine-7-one [ka]

[0215] Following the synthesis method in Reference Example 3, 6-(6-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 55 was synthesized. MS m / z (ESI): 467.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.75(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).

[0216] Example 56 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0217] Following the synthesis method in Reference Example 3, 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 56 was synthesized. MS m / z (ESI): 493.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.75(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).

[0218] Example 56 can also be synthesized by the following method. [ka]

[0219] Step 1: Under nitrogen gas protection, 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-bisdiphenylphosphino-9,9-dimethylxanthene (219.2 mg, 0.38 mmol) were dissolved in 1'4-dioxane (10 mL), heated to 130°C by microwave, and reacted 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) to obtain tert-butyl N-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]amino]cyclopentyl]carbamate 56a (170 mg), with a yield of 46.8%. MS m / z (ESI): 384.2[M+H] + .

[0220] Step 2: At room temperature, 56a (170 mg, 0.44 mmol) was dissolved in methanol (7 mL), hydrochloric acid (4 M, 4 mL) was added, and the mixture was stirred 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 obtain (1S,3S)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]cyclopentan-1,3-diamine 56b (120 mg), with a yield of 95.5%. MS m / z (ESI): 284.2[M+H] + .

[0221] Step 3: At room temperature, 56b (140 mg, 0.49 mmol), 2-fluoro-5-nitropyridine (77.2 mg, 0.54 mmol), and cesium carbonate (322.0 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), heated to 80°C, and stirred for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system A) to obtain (1S,3S)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-N1-(5-nitro-2-pyridyl)cyclopentan-1,3-diamine 56c (50 mg), with a yield of 25.0%. MS m / z (ESI): 406.2[M+H] + .

[0222] Step 4: Under a hydrogen gas atmosphere, 56c (50 mg, 0.12 mmol) and palladium 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 obtain N2-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]amino]cyclopentyl]pyridine-2,5-diamine 56d (35 mg), with a yield of 75.6%. MS m / z (ESI): 376.1[M+H] + .

[0223] Step 5: At room temperature, 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), the temperature was raised to 50°C, and the mixture was stirred for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative thin-layer chromatography (elution system A) to obtain 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 56 (11 mg), with a yield of 24.0%. MS m / z (ESI): 493.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.75(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).

[0224] Example 57 4-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one [ka]

[0225] Step 1: At room temperature, 3 g (100 mg, 0.26 mmol) of the reference example, 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), and the mixture was stirred for 16 hours. The reaction mixture was filtered, concentrated, and the residue purified by silica gel column chromatography (elution system A) to obtain 4-chloro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one 57a (90 mg), with a yield of 64.21%. MS m / z (ESI): 529.1[M+H] + .

[0226] Step 2: Under nitrogen gas protection, 57a (90 mg, 0.17 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriboloxane in a tetrahydrofuran solution (3 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), the mixture was heated to 100°C, and stirred for 5 hours. The reaction mixture was concentrated, and the residue was purified by thin-layer chromatography (elution system A) to obtain 4-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one 57 (56.6 mg), with a yield of 65.41%. MS m / z (ESI): 509.1[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0227] Example 58 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5-azaspiro[2,4]heptan-4-one [ka]

[0228] Step 1: Add 3 g (70 mg, 0.19 mmol) of the reference example to a solution of p-toluenesulfonic acid (96 mg, 0.56 mmol) in acetonitrile (1.5 mL). Cool the reaction mixture to 0°C. Add sodium nitrite (26 mg, 0.37 mmol) and potassium iodide (80 mg, 0.48 mmol) in water (0.5 mL) to the reaction mixture. Raise the temperature to room temperature and stir for 48 hours. Saturated sodium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain (1S,3S)-N1-(5-iodopyridine-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 58a (37 mg). The yield was 40.85%. MS m / z (ESI): 489.1[M+H] + .

[0229] Step 2: Referring to the synthesis method of Example 32, the 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5-azaspiro[2,4]heptan-4-one 58 was synthesized. MS m / z (ESI): 472.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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,1H),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).

[0230] Example 59 4,6-dimethyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one [ka]

[0231] Following the synthesis method in Reference Example 3, 4,6-dimethyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one 59 was synthesized. MS m / z (ESI): 523.2[M+H] + .

[0232] Example 60 3-Methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)methylpicolinamide [ka]

[0233] Step 1: Reference example 3 g (50 mg, 0.13 mmol), 3-methyl-2-pyridinecarboxylic acid (20 mg, 0.15 mmol), and N-methylimidazole (33 mg, 0.4 mmol) were dissolved in acetonitrile (1.5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.2 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. Saturated sodium chloride solution (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried, concentrated, and the residue was separated by reverse-phase HPLC to obtain 3-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)methylpicolinamide 60 (9.7 mg), with a yield of 14.75%. MS m / z (ESI): 497.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.26(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).

[0234] Example 61 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0235] Following the synthesis method in Reference Example 3, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 61 was synthesized. MS m / z (ESI): 513.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.87-8.76(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).

[0236] Example 62 N-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)methylpicolinamide [ka]

[0237] Step 1: Dissolve 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) in acetonitrile (15 mL). Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.88 g, 6.69 mmol) to the reaction mixture and stir at room temperature for 3 hours. Saturated sodium chloride solution (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried, and concentrated. Petroleum ether / ethyl acetate (v / v=1 / 1, 10 mL) was added to the residue, and the mixture was stirred at 60°C for 30 minutes. After cooling to room temperature and filtering, N-(6-fluoropyridine-3-yl)methylpicolinamide 62b (464 mg) was obtained, with a yield of 47.90%. MS m / z (ESI): 218.1[M+H] + .

[0238] Step 2: Sodium hydride (128 mg, 3.20 mmol, 60% content) was added to a 10 mL solution of 62b (464 mg, 2.14 mmol) in tetrahydrofuran at 0°C. After 30 minutes, iodomethane (606 mg, 4.27 mmol) was added to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 1.5 hours. Saturated sodium chloride solution (20 mL) was added to the reaction mixture, 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 obtain N-(6-fluoropyridine-3-yl)-N-methylmethylpicolinamide 62c (53 mg). The yield was 10.73%. MS m / z (ESI): 232.1[M+H] + .

[0239] 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), and the reaction was heated to 130 °C and stirred for 60 hours. The reaction mixture was filtered, and the filtrate was separated by reverse-phase HPLC to obtain N-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)methylpicolinamide 62 (4.2 mg), with a yield of 4.73%. MS m / z (ESI): 497.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.80(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),7.17-7.11(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).

[0240] Example 63 3-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0241] Referencing the synthesis method of Example 58, the compound was synthesized to obtain 3-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 63. MS m / z (ESI): 514.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0242] Example 65 5-Carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile [ka]

[0243] Following the synthesis method in Reference Example 3, 5-carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonitrile 65 was synthesized. MS m / z (ESI): 520.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 9.24(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).

[0244] Example 66 1-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile [ka]

[0245] Following the synthesis method in Reference Example 3, 1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile 66 was synthesized. MS m / z (ESI): 520.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 9.12(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).

[0246] Example 67 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0247] Following the synthesis method in Reference Example 3, 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 67 was synthesized. MS m / z (ESI): 509.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(d,1H),8.35 (d,1H),8.0(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).

[0248] Example 68 2-Cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0249] Following the synthesis method in Reference Example 3, 2-cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 68 was synthesized. MS m / z (ESI): 535.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0250] Example 69 (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3,4]octan-5-yl)pyridine-2-yl)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine [ka]

[0251] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3,4]octan-5-yl)pyridine-2-yl)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 69 was synthesized by referring to the synthesis method of Example 58. MS m / z (ESI): 424.2[M+H] + .

[0252] Example 70 (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3,4]octan-5-yl)pyridine-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine [ka]

[0253] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3,4]octan-5-yl)pyridine-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 70 was synthesized by referring to the synthesis method of Example 58. MS m / z (ESI): 474.2[M+H] + .

[0254] Example 71 6-Cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one [ka]

[0255] Following the synthesis method in Reference Example 3, 6-cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one 71 was synthesized. MS m / z (ESI): 535.2[M+H] + .

[0256] Example 72 3-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile [ka]

[0257] Following the synthesis method in Reference Example 3, 3-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile 72 was synthesized. MS m / z (ESI): 520.2[M+H] + .

[0258] Example 73 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridine]-2(1H)-one [ka]

[0259] Following the synthesis method of Example 31, 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridine]-2(1H)-one 73 was synthesized. MS m / z (ESI): 456.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 11.63(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).

[0260] Example 75 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one [ka]

[0261] Following the synthesis method in Reference Example 3, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one 75 was synthesized. MS m / z (ESI): 513.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.87-8.76(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).

[0262] Example 76 1-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile [ka]

[0263] Following the synthesis method in Reference Example 3, 1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile 76 was synthesized. MS m / z (ESI): 520.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.94(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),6.78(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).

[0264] Example 77 3-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile [ka]

[0265] Following the synthesis method in Reference Example 3, 3-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile 77 was synthesized. MS m / z (ESI): 520.2[M+H] + .

[0266] Example 78 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)pyrimidine-2(1H)-one [ka]

[0267] Referencing the synthesis method of Example 58, 4-hydroxy-1-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)pyrimidine-2(1H)-one 78 was synthesized. MS m / z (ESI): 473.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 11.37(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).

[0268] Example 79 5-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0269] Step 1: Under nitrogen gas protection, 2-benzyloxy-5-bromopyridine 79a (2.0 g, 7.57 mmol), 3-pyrazolecarboxylate methyl (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 was heated to 120 °C and stirred for 5 hours. After diluting the reaction mixture with ethyl acetate, it was washed with saturated brine, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1-(6-(benzyloxy)pyridine-3-yl)-1H-pyrazole-3-carboxylate methyl 79b (230 mg). The yield was 9.8%. MS m / z (ESI): 310.1[M+H] + .

[0270] Step 2: Under a hydrogen gas atmosphere, 79b (230 mg, 0.743 mmol) and palladium carbon (27 mg, 0.223 mmol) were dissolved in methanol (5 mL), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered, dried, and concentrated to obtain 1-(6-oxo-1,6-dihydropyridine-3-yl)-1H-pyrazole-3-carboxylate methyl 79c (60 mg), with a yield of 36.8%. MS m / z (ESI): 220.1[M+H] + .

[0271] Step 3: Under nitrogen gas protection, 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), and the reaction was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1-(2-oxo-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-5-yl)-1H-pyrazole-3-carboxylate methyl 79d (60 mg). The yield was 84.3%. MS m / z (ESI): 580.2[M+H] + .

[0272] Step 4: Under nitrogen gas protection, 79d (60 mg, 0.103 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) at 0°C. A solution of methylmagnesium bromide in tetrahydrofuran (1 M, 0.5 mL) was added dropwise to the reaction mixture, and the reaction was heated to room temperature and stirred for 1 hour. The reaction was quenched with methanol, concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 5-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 79 (10.0 mg), with a yield of 16.7%. MS m / z (ESI): 580.2[M+H] + .

[0273] 1H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0274] Example 81 4-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0275] The target product 4-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 81 was synthesized by referring to the synthesis method of Example 58. MS m / z (ESI): 514.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0276] Example 82 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one [ka]

[0277] Following the synthesis method in Reference Example 3, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one 82 was synthesized. MS m / z (ESI): 508.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0278] Example 83 6-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one [ka]

[0279] Following the synthesis method in Reference Example 3, 6-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one 83 was synthesized. MS m / z (ESI): 512.2[M+H] + .

[0280] Example 84 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one [ka]

[0281] Following the synthesis method in Reference Example 3, 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one 84 was synthesized. MS m / z (ESI): 494.2[M+H] + .

[0282] Example 85 5-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one [ka]

[0283] Following the synthesis method in Reference Example 3, 5-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one 85 was synthesized. MS m / z (ESI): 508.2[M+H] + .

[0284] Example 86 5-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one [ka]

[0285] Following the synthesis method in Reference Example 3, 5-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)isodihydroindole-1-one 86 was synthesized. MS m / z (ESI): 512.2[M+H] + .

[0286] Example 88 7-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one [ka]

[0287] Following the synthesis method in Reference Example 3, 7-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one 88 was synthesized. MS m / z (ESI): 513.2[M+H] + .

[0288] Example 89 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one [ka]

[0289] Following the synthesis method in Reference Example 3, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one 89 was synthesized. MS m / z (ESI): 509.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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,1 H),4.94(s,2H),4.38-4.1(m,2H),2.61(s,3H),2.22-2.11(m,2H),2.01-1.85(m,2H),1.63-1.47(m,2H).

[0290] Example 90 6-methyl-1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile [ka]

[0291] Following the synthesis method in Reference Example 3, 6-methyl-1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile 90 was synthesized. MS m / z (ESI): 534.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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),6.56(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).

[0292] Example 91 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0293] Following the synthesis method in Reference Example 3, 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 91 was synthesized. MS m / z (ESI): 509.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0294] Example 112 6-(5-fluoro-6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)pyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0295] Step 1: Reference Example 3e (150 mg, 0.53 mmol), 2,3-difluoro-5-nitropyridine (93 mg, 0.58 mmol), and cesium carbonate (428 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 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-(3-fluoro-5-nitro-2-pyridyl)-N3-[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]cyclopentan-1,3-diamine 112a (180 mg), with a yield of 80.5%. MS m / z (ESI): 426.1[M+H] + .

[0296] Step 2: Under a hydrogen gas atmosphere, 112a (158 mg, 0.37 mmol) and palladium / carbon (40 mg, 0.037 mmol, content: 10%) were dissolved in methanol (10 mL), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 3-fluoro-N2-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]amino]cyclopentyl]pyridine-2,5-diamine 112b (131 mg), with a yield of 88.5%. MS m / z (ESI): 396.1[M+H] + .

[0297] Step 3: 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) were dissolved in a mixed solvent of n-butanol (6 mL) and N,N-dimethylformamide (0.5 mL). The mixture was heated to 40°C and stirred for 11 hours, then heated to 110°C and stirred for another 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 112 (100.4 mg). The yield was 70.7%. MS m / z (ESI): 513.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82(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).

[0298] Example 114 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-6,7-dihydro-5H-pyrrole[3,4-b]pyridine-5-one-7,7-d2 [ka]

[0299] Example 12 (30 mg, 0.061 mmol) was dissolved in tetrahydrofuran (2 mL) and heavy water (1 mL), and a heavy water solution of 40% sodium deuter hydroxide (62 mg, 0.607 mmol) was added. The mixture was heated to 35°C under nitrogen gas protection and stirred for 16 hours. The reaction mixture was cooled to room temperature, added to 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 obtain 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazole[1,5-a]pyridine-2-yl)amino)cyclopentylamino)pyridine-3-yl)-6,7-dihydro-5H-pyrrole[3,4-b]pyridine-5-one-7,7-d2 114 (8.7 mg), with a yield of 28.9%.

[0300] MS m / z (ESI): 497.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.83-8.79(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,1H),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).

[0301] Example 164 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)aminopyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one [ka]

[0302] Step 1: Under nitrogen gas 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 the reaction was 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-nitropyridine-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 164a (200 mg) was obtained, with a yield of 87%. MS m / z (ESI): 376.2 [M+H] + .

[0303] Step 2: Under a hydrogen gas 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 obtain 3-fluoro-N 2 -((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 164b (170 mg) was obtained, with a yield of 97%. MS m / z (ESI): 346.2[M+H] + .

[0304] Step 3: Under nitrogen gas protection, 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)pyridinecarboxylate (50 mg, 0.23 mmol) was added while stirring, and the reaction was stirred at 25°C for 16 hours, after which the temperature was raised to 85°C and stirred for another 16 hours. The reaction was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)aminopyridine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 164 (20 mg), with a yield of 17%. MS m / z (ESI): 463.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.76(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).

[0305] Example 186 5'-Fluoro-6'-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0306] Step 1: 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) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 100 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain (1S,3S)-N 1 -(5-bromo-3-fluoropyridine-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)cyclopentan-1,3-diamine 186a (75 mg) was obtained, with a yield of 71.86%. MS m / z (ESI): 409.1[M+H] + .

[0307] Step 2: Under nitrogen gas 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), and the reaction was heated to 120 °C and stirred for 16 hours. Saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (25 mL x 2), the organic phase was combined, dried, concentrated, and the residue was separated by reverse-phase HPLC (formic acid system) to obtain 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 186 (27.9 mg), with a yield of 35.95%. MS m / z (ESI): 424.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.71-8.61(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).

[0308] Example 418 6'-(((1S,3S)-3-((6-(3-hydroxyazetidine-1-yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0309] Example 418 can also be manufactured by referring to the method described below. [ka]

[0310] Step 1: At room temperature, 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine 418a (500 mg, 1.87 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium borohydride (141.7 mg, 3.75 mmol) was added while stirring, followed by isopropanol (0.5 mL), and the mixture was stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Dichloromethane (20 mL) was added and dissolved, and 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 mixture, the organic phase was washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain 6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine 418b (320 mg). The yield was 73.5%. MS m / z (ESI): 232.0[M+H] + .

[0311] 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 obtain 6'-(((1S,3S)-3-((6-bromopyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 418c (300 mg). The yield was 88.0%. MS m / z (ESI): 466.1[M+H] + .

[0312] Step 3: Under nitrogen gas 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), heated to 100°C, and stirred for 16 hours. The reaction mixture was filtered and purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product 6'-(((1S,3S)-3-((6-(3-hydroxyazetidine-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 418 (15 mg), with a yield of 15.3%. MS m / z (ESI): 459.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.46(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),5.5 5(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).

[0313] Example 422 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidine-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one [ka]

[0314] Referencing the synthesis method of Example 418, the compound was synthesized to obtain 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidine-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 422. MS m / z (ESI): 473.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.46(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).

[0315] The synthesis method for the example may be described by referring to the example above.

[0316] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0317] The nuclear magnetic characterization data for related examples are shown in the table below.

[0318] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0319] Biological Test Evaluation The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0320] Laboratory equipment and reagents: 1. Instruments: Envision (PE-Cisbio:2105-0020), Incubator (Boxun, BC-J80S), Centrifuge (Eppendorf:5810R, Centrifuge 5720R), Ice maker (Xueke Electric, IMS-150), Pure water system (THERMO: Pacific TII+Micropure), Envision (PE-Cisbio:2105-0020), Plate washer (Thermo:WELLWASH VERSA), Microwell plate shaker (Thermo:88882006), Refrigerator (BCD-268TN, Haier), Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory), Clean bench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.), 5mL pipette (Research Plus, Eppendorf), 1mL pipette (Research Plus (Eppendorf), constant temperature water bath (HWS-12, Shanghai Yiheng Science), electronic balance (BSA2202S-CW, CPA2202S, Sartorius), ultrasonic cleaner (115F0032, Shanghai Science and Technology), magnetic stirrer (08-2G, Chikyu), fully automatic biochemical analyzer (Hitachi 7180, HITACHI).

[0321] 2. Reagents: PCSK9-His (Sino biology, 29698-H08H), Anti-His Tb (Revvity, 61HISTLF), probe compound (Alexa Fluor 647 labeled, Hansoh synthesis), 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 loading tank (Corning, 4870), 50 mL centrifuge tube (Corning, 430829), 2.5 μL Pipette (Eppendorf, I36630F), 10uL pipette (Eppendorf, J13131F), 100uL pipette (Eppendorf, R22267J), 1000uL pipette (Eppendorf, I44804F), 10uL 12-channel electronic pipette (METTLER TOLEDO, 17013797), 300uL 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 cleavage solution (Thermo: 78503), protease inhibitor (Pierce: 78430), Alamethicin (Abcam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Guanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4) NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bide Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck), high-fat feed (Western Diet, D12079B), physiological saline (MA0083-D, meilunbio), Solutol HS 15 (102483882, Sigma).

[0322] 1. Bonding experiment Test Example 1. Measurement of the binding ability of the compound of the present invention to the PCSK9 protein. 1. Experimental Objective: To detect the binding activity of compounds to the PCSK9 protein using the HTRF method.

[0323] 2. Experimental method: 1) Prepare a 1x experimental buffer solution consisting of 20 mM HEPES, 150 mM NaCl, 1 mM CaCl2, 0.01% Tween20, and 0.01% BSA. 2) Prepare a 2.5x final concentration PCSK9-His working solution (30 nM) using 1x experimental buffer, add 8 μL of the protein solution to each well of a 384-well plate excluding the low control, and add 8 μL of 1x experimental buffer to the low control well. 3) Preparation of compound working solution: First, the compound in the stock solution is uniformly serially diluted with DMSO (300 μM top, 3-fold, 10 doses). Then, 3.33 μL of each serially diluted compound is pipetted and added to 96.7 μL of 1x experimental buffer. The mixture is thoroughly and uniformly mixed to obtain the prepared compound working solution (10x). 4) Aspirate 2 μL of the compound, place it in the corresponding well, and incubate at 25°C for 10 minutes. 5) Prepare a 4x final concentration probe compound working solution (90 nM) using 1x experimental buffer, mix thoroughly and uniformly, add 5 μL to each well, and incubate at 25°C for 10 minutes. 6) Prepare a 4x final concentration Anti-His Tb working solution (4x) using 1x experimental buffer, add 5 μL to each well, and incubate at 25°C for 2 hours. 7) The HTRF665 / 615 program was read using Envision.

[0324] 3. Method of processing experimental data: Using the XLfit4 parameter log(inhibitor) vs. response -- Variable slope (four parameters), nonlinear fitting is performed on the compound concentration and the corresponding inhibition rate, and IC is calculated. 50 I calculated it. 4. Experimental results:

[0325] [Table 3]

[0326] 5. Experimental Conclusion: As can be seen from the data in the table, the compounds of the examples shown in the present invention have a remarkable binding effect on the PCSK-9 protein.

[0327] Two-cell function experiments Test Example 1. Measurement of the effect of the compound of the present invention on the concentration of PCSK9 secreted from HepG2 cells. 1. Experimental Objective: To detect the inhibitory effect of compounds on PCSK9.

[0328] 2. Experimental method: 1) HepG2 cell lines were cultured in complete medium at 37°C and 5% CO2 until a fusion degree of 70% to 90% was achieved.

[0329] 2) The cells were digested, resuspended in experimental medium, and inoculated into 96-well cell culture plates at a rate of 25,000 cells / well / 200 μL. The cells were then cultured at 37°C and 5% CO2 for 20-24 hours.

[0330] 3) Remove the culture medium from the cell culture plate, add 200 μl of experimental medium to each well, and wash once.

[0331] 4) Preparation of positive control compounds and test compounds: The positive control compounds and test compounds were diluted on compound plates.

[0332] 5) The diluted compound was added to the cell culture plate at a rate of 250 μL per well and incubated at 37°C in 5% CO2 for 48 hours.

[0333] 6) Cell culture medium was collected in 200 μL per well and stored frozen at -80°C for use.

[0334] 7) The cell culture samples were removed from -80°C, dissolved, vortexed, centrifuged, and prepared for use.

[0335] 8) Setting the standard curve: Dilution buffer of the corresponding volume was added sequentially to each standard tube, and the standard samples were sequentially diluted by taking the corresponding volume from the original tube or the tube of the previous concentration in the order of concentrations 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, and 0 ng / mL.

[0336] 9) Washing solution formulation: 10x Wash buffer was diluted to 1x with Milli-Q and prepared for use.

[0337] 10) Following the standard curve wells and sample wells established by the plate map, 100 μL each of the corresponding standard and culture medium sample was added to each well. A seal sheet was applied, the mixture was placed in a shaker, and it was mixed uniformly by gentle shaking at room temperature and incubated for 1 hour.

[0338] 11) The plate was placed in the plate washing device, the washing solution was set to 350 μL per well, and the plate washing was repeated four times.

[0339] 12) Add 100 μL of HRP-conjugated detection antibody to each well, cover with a seal sheet, place in a shaker, mix thoroughly and uniformly, and incubate for 1 hour.

[0340] 13) The plate was placed in the plate washing device, the washing solution was set to 350 μL per well, and the plate washing was repeated four times.

[0341] 14) Add 100 μL of Substrate reagent to each well, protect from light, cover with a sealing sheet, place in a shaker, mix thoroughly and uniformly, and incubate for 10-20 minutes.

[0342] 15) Add 100 μL of stop solution (1N H2SO4) to each well and mix uniformly.

[0343] 16) The optical density (OD) values ​​of each well were sequentially measured using a microplate reader at a wavelength of 450 nm. Detection was performed within 30 minutes after the completion of the reaction.

[0344] 3. Processing of experimental data: OD values ​​were read using a microplate reader. The actual values ​​for each well were obtained by subtracting the OD value of the standard group at concentration 0 from the OD values ​​of the standard, control group, and sample. A standard curve was plotted using Graphpad, and the sample concentration was calculated. If dilution was performed before sample detection, the actual sample concentration was obtained by multiplying by the corresponding dilution factor at the end of the calculation. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to various concentrations, plotting was performed using Graphpad, and the IC50 was obtained. 4. Experimental results:

[0345] [Table 4]

[0346] 5. Experimental Conclusion: As can be seen from the data in the table, the compounds of the examples shown in the present invention showed a strong inhibitory effect in experiments on the concentration of PCSK9 secreted from HepG2 cells.

[0347] Test Example 2. Measurement of the effect of the compound of the present invention on HepG2 cell LDLR levels. 1. Experimental Objective: To detect the effect of compounds on LDLR protein levels.

[0348] 2. Experimental method: 1) HepG2 cell lines were cultured in complete medium at 37°C and 5% CO2 until a fusion degree of 70% to 90% was achieved.

[0349] 2) The cells were digested, resuspended in experimental medium, and inoculated into 96-well cell culture plates at a rate of 25,000 cells / well / 200 μL. The cells were then cultured at 37°C and 5% CO2 for 20-24 hours.

[0350] 3) Remove the culture medium from the cell culture plate, add 200 μL of experimental medium to each well, and wash once.

[0351] 4) Preparation of positive control compounds and test compounds: The positive control compounds and test compounds were diluted on compound plates.

[0352] 5) The diluted compound was added to the cell culture plate at a rate of 250 μL per well and incubated at 37°C in 5% CO2 for 48 hours.

[0353] 6) Remove the cell medium, wash the cells with PBS, and add 50 pL of cell cleavage fluid and a protein inhibitor.

[0354] 7) The sample was centrifuged, the cleaved material was removed, and the sample was stored and prepared for use.

[0355] 8) Setting the standard curve: Dilution buffer of the corresponding volume was added sequentially to each standard tube, and the standard sample was sequentially diluted by taking the corresponding volume from the original tube or the previous concentration tube.

[0356] 9) Washing solution formulation: 10x Wash buffer was diluted to 1x with Milli-Q and prepared for use.

[0357] 10) According to the standard curve wells and sample wells established by the plate map, 80 μL of the corresponding standard and sample were added to each well twice. Wells to which no standard was added were designated as background value wells. Seal sheets were applied, the mixtures were placed in a shaker, and the mixtures were heated gently at room temperature to ensure uniform mixing, and incubated for 2 hours.

[0358] 11) The plate was placed in the plate washing device, the washing solution was set to 350 μL per well, and the plate washing was repeated four times.

[0359] 12) Add 200 μL of human LDLR conjugate to each well, cover with a seal sheet, place in a shaker, mix thoroughly and uniformly, and incubate for 2 hours.

[0360] 13) The plate was placed in the plate washing device, the washing solution was set to 350 μL per well, and the plate washing was repeated four times.

[0361] 14) Add 200 μL of Substrate solution to each well, shield from light, cover with a sealing sheet, place in a shaker, mix thoroughly and uniformly, and incubate for 20 minutes.

[0362] 15) Add 50 μL of stop solution to each well and mix uniformly for 20 minutes.

[0363] 16) The optical density OD values ​​of each well were sequentially measured using a microplate reader at a wavelength of 450 nm.

[0364] 3. Processing of experimental data: OD values ​​were read using a microplate reader. The actual values ​​for each well were obtained by subtracting the OD value of the standard group at concentration 0 from the OD values ​​of the standard, control group, and sample. A standard curve was plotted using Graphpad, and the sample concentration was calculated. If dilution was performed during sample detection, the actual sample concentration was obtained by multiplying by the corresponding dilution factor at the end of the calculation. Concentration increase percentage % = (actual control concentration - actual sample concentration) / actual control concentration * 100. 4. Experimental results:

[0365] [Table 5]

[0366] 5. Experimental Conclusion: As can be seen from the data in the table, the compounds of the examples shown in the present invention demonstrated a significant improvement in LDLR concentration in experiments on the effect on HepG2 cell LDLR concentration.

[0367] III. Pharmacokinetic Experiments Test Example 1. Pharmacokinetic Measurement in Mice 1. Experimental Objective: Using C57BL / 6J mice as test animals, we investigated the pharmacokinetic behavior of the compound of the present invention in mouse bodies (plasma) after oral or intravenous administration.

[0368] 2. Test Scheme 2.1 Test chemicals: Compounds of the present invention, prepared in-house.

[0369] 2.2 Test animals: C57 mouse, male, Shanghai Bikai Laboratory Animal Co., Ltd., Animal production license number (SCXK(Shanghai)2013-0006 N0.311620400001794).

[0370] 2.3 Drug preparation: Preparation of orally administered drugs: 10% Solutol HS15 10 g of Solutol HS15 solid was weighed, dissolved in 90 mL of purified water, mixed, and stirred uniformly, then sonicated to obtain a clarified solution. The compound of the present invention was weighed, dissolved in the solution, shaken well, and sonicated for 15 minutes to obtain a colorless clarified solution with a concentration of 0.5 mg / mL. Preparation of intravenous drug: 5% DMSO + 10% Solutol HS15 + 85% PBS. The compound of the present invention was weighed, and according to the proportion of the total volume to be administered, 5% DMSO was first added, vortexed, and sonicated for 2 minutes to completely dissolve it. Next, 10% Solutol HS15 was added, vortexed, and sonicated for 2 minutes to completely dissolve it. Finally, 85% PBS was added, vortexed, and sonicated for 5 minutes. The solution was then passed through a 0.22 μm filter membrane to obtain a colorless, clear clarified solution with a concentration of 0.2 mg / mL.

[0371] 2.4 Administration: Three male C57 mice were administered PO after overnight fasting, with a dose of 5 mg / kg and a volume of 10 mL / kg. Three male C57 mice were administered IV after overnight fasting, with a dose of 1 mg / kg and a volume of 5 mL / kg.

[0372] 2.5 Sample Collection: 0.04 mL of orbital blood was collected from mice before administration and at 0.083(iv), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 test tube, the plasma was centrifuged at 4°C and 6000 rpm for 6 minutes, stored at -80°C, and fed 4 hours after administration.

[0373] 2.6 Measurement Results: The final measurement results were obtained using the LCMS / MS method.

[0374] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0375] [Table 6]

[0376] 4. Experimental conclusion: According to pharmacokinetic measurements in C57BL / 6J mice, the compound of the present invention showed favorable PK advantages.

[0377] Test Example 2. Pharmacokinetic Measurement in Cynomolgus Monkeys 1. Research Objective: Using cynomolgus monkeys as test animals, we investigated the pharmacokinetic behavior of the compound of the present invention in the body (plasma) of cynomolgus monkeys when administered orally at a dose of 5 mg / kg.

[0378] 2. Experimental plan: 2.1 Experimental chemicals: Compounds used in the examples of the present invention, prepared in-house.

[0379] 2.2 Experimental animals: Cynomolgus macaques, 3 males per group, Guangxi Xiongsen, Animal production permit number: SCXK(Guangxi)2021-0004).

[0380] 2.3 Formulation: Preparation of orally administered drugs: 10% Solutol HS15 in water 10 g of solid Solutol HS15 was weighed, added to 90 ml of ddH2O, placed in a 100 ml volumetric flask, vortexed to mix uniformly, and sonicated to obtain a clarified solution. The compound was weighed, placed in a 100 ml glass bottle, the solution was added, vortexed, and sonicated for 10 minutes to obtain a white suspension with a concentration of 1 mg / mL.

[0381] 2.4 Administration: Three male cynomolgus monkeys were given oral administration (PO) after fasting overnight. The dose was 5 mg / kg, and the volume of administration was 5 mL / kg.

[0382] 2.5 Sample Collection: Blood Collection: 0.3 mL of blood was collected from the forelimb veins of cynomolgus monkeys before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulation tube, centrifuged at 4°C and 6000 rpm for 6 minutes to separate the plasma, stored at -80°C, and fed 4 hours after administration.

[0383] 2.6 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile and allowed to precipitate. After mixing, the mixture was centrifuged at 3500 × g for 5 to 20 minutes.

[0384] 2) The treated supernatant solution was taken, and the concentration of the test compound was analyzed by LC / MS / MS. The LC / MS / MS analyzer used was an AB Sciex API 4000 Qtrap.

[0385] ● Liquid-phase analysis: Liquid-phase conditions: Shimadzu LC-20AD pump ● Chromatography column: Agilent ZORBAX XDB-C18 (50 × 2.1 mm, 3.5 μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, and Solution B is acetonitrile. Flow rate: 0.4 mL / min ● The elution time was 0 to 4.0 minutes, and the eluate was as follows:

[0386] [Table 7]

[0387] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0388] 4. Experimental Conclusion: According to pharmacokinetic measurements in cynomolgus monkeys, the compound of the present invention exhibits good PK advantages, and here, the compound AUC 0-∞ The (ng / mL × h) is between 20,000 and 50,000, and the AUC of the dominant compound is 0-∞ The (ng / mL × h) value was shown to be between 30,000 and 50,000.

[0389] Test Example 3. Investigation of in vitro metabolic stability of the compound of the present invention in mouse, rat, and human liver microsomes. 1. Experimental Objective: The objective of this study was to evaluate the metabolic stability of the compound in phase I and partial phase II in mouse, rat, and human liver microsomes.

[0390] 2. Experimental Plan 2.1 Drug Preparation: The compound of the present invention was prepared as a 10 mM stock solution with DMSO (or other suitable solution) and stored in a refrigerator at -20°C for use. The compound of the present invention was prepared in-house.

[0391] 2.2 Experiment Steps 1) Preparation of buffer solution: 4.01 mL of 1 M K2HPO4·3H2O (AR grade) and 0.99 mL of 1 M KH2PO4 (AR grade) were taken, dissolved in ultrapure water, and the volume was adjusted to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0392] 2) Preparation of compound working solution: Preparation of compound working solution: 998 μL of phosphate buffer was added to 2 μL of compound stock solution, resulting in a final concentration of 20 μM. Depending on the properties of the compound, the preparation ratio may be appropriately adjusted to control the final concentration.

[0393] 3) Preparation of liver microsomal agonist: 156.3 μL of 20 mg / mL microsomes were diluted with 100 mM phosphate buffer to 5 mL and mixed uniformly, resulting in a final concentration of 0.625 mg / mL.

[0394] 4) Preparation of NADPH and UDPGA: 33.3 mg of NADPH and 25.8 mg of UDPGA were weighed out, and 2 mL of 100 mM phosphate buffer was added to obtain a final concentration of 20 mM for both.

[0395] 5) Preparation of the puncture-opening agent (Alamethicin): 1 mg of Alamethicin was weighed, and 200 μL of methanol was added to prepare a 5 mg / mL solution. Further, 10 μL was taken from this solution and added to 990 μL of phosphate buffer (pH 7.4), resulting in a final concentration of 50 μg / mL.

[0396] 6) Preparation of stop solution: The internal standard was diluted with acetonitrile (or other suitable solution) to prepare the stop solution, which was stored in a refrigerator at 2-8°C.

[0397] 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 sequentially added to a 96-well plate and pre-incubated at 37°C for 10 minutes. Subsequently, 50 μL of prepared NADPH / UDPGA was added to initiate the reaction, and the mixture was incubated at 37°C until the total volume of the reaction system was 500 μL, with the final content of each component as follows.

[0398] [Table 8]

[0399] 50 μL samples were taken at 0, 5, 15, 30, 60, and 120 mins, 200 μL of cold stop solution containing an internal standard was added to stop the reaction of the samples, and the samples were centrifuged at 3500 rpm for 10 mins. The supernatant was taken and LC-MS / MS analysis was performed.

[0400] 2.4 Chromatographic Analysis 1) Chromatography conditions: Instrument: Shimadzu LC-20 AD, Chromatography column: Phenomenex Gamin™ C18 (50*4.6mm, 5μm particle size), Mobile phase: A: 0.1% formic acid aqueous solution, B: Acetonitrile, Flash gradient: 0.2~1.6min 5%A~95%A, 3.0~3.1min 95%A~5%A, Flow rate: 1.0 ml / min, Run time: 4.0 min, Sample input volume: 5 μL.

[0401] 2) Mass spectrometry conditions Instrument: API 4000 liquid chromatography-mass spectrometer, AB Sciex; Ion source: Electrospray ionization source (ESI); Dry gas: N2; Temperature: 500°C; Electrospray voltage: 5000V; Detection method: Cation detection; Scanning method: Reaction monitoring (MRM) method; Scanning time: 0.8401s.

[0402] 3. Data processing: The raw data was calculated using the following formula. Remaining percentage % = Peak area ratio of compound to internal standard at any point in time / Peak area ratio of compound to internal standard at 0 minutes × 100 T 1 / 2 = 0.693 / Ke, where Ke represents the removal rate constant.

[0403] Ke-mediated in vitro liver microsome-specific clearance (CL) int ) and hepatic intrinsic clearance (CL) int,liver ) calculation CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation in mg / mL) CL int,liver =CL int × Amount of microsomal protein in the liver (mg / g) × Liver weight-to-body weight ratio Based on the well-stirred model, in vivo liver clearance (CL) int,liver ) was estimated.

[0404] CL=(CL int,liver× fu×Qh) / (CL int,liver× fu + Qh), where fu represents the free score in the blood and is 1 by default. The parameters in the formula are shown in the table below.

[0405] [Table 9] 4. Experimental results:

[0406] [Table 10]

[0407] 5. Experimental Conclusion: The results show that the compounds of the preferred examples of the present invention exhibit stable metabolic effects in liver microsomes of each genera, and particularly in human liver microsomes.

[0408] IV. Experiments on drug efficacy Test Example 1. In vivo pharmacodynamic studies of the compound of the present invention in a B6-hPCSK9 transgenic mouse hyperlipidemia animal model. 1. Experimental Objective: To evaluate the in vivo efficacy of the compound in a B6-hPCSK9 transgenic mouse animal model of hyperlipidemia.

[0409] 2. Experimental Procedures and Data Processing 2.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0410] 2.2 Animal Model: After the animals reached the barrier system, they were acclimatized for one week and then fed a high-fat diet. Body weight and feed intake were weighed once a week, and the animals' body weight and food intake were recorded.

[0411] 2.3 Grouping and Administration a. The subjects were grouped using a random grouping method.

[0412] c. Based on the group assignment results, administration of the test drug was initiated (method of administration: oral administration, volume of administration: 10 mL / kg, frequency of administration: once / day or single dose, administration cycle: 21 days, vehicle: 10% Solutol HS 15 / 90% Saline). Test drug: compound of the present invention, manufactured in-house.

[0413] d. After the start of administration of the test drug, body weight and feed intake were weighed twice a week, and blood samples were taken once a week.

[0414] e. Data was processed using software such as Excel. Weight change rate BWC (%) = (Body weight at the end of animal treatment - Body weight at the start of animal treatment) / Body weight at the start of animal treatment × 100%, Food intake (g / mice / day) = (Previous feed addition amount + Previous feed remaining amount - Current feed remaining amount) / Number of animals / Number of feeding days, Calculation of biochemical inhibition rate: Using the biochemical results of the Vehicle group detected in the same lot as the baseline, the data for each administration group was normalized, and the percentages of TC and LDL-C were calculated according to the formulas, TC change percentage (%) = (Post-administration TC value - Pre-administration TC value) / Pre-administration TC value * 100%, LDL-C change percentage (%) = (Post-administration LDL-C value - Pre-administration LDL-C value) / Pre-administration LDL-C value * 100%. PCSK9 in plasma was detected by ELISA. 3. Experimental results:

[0415] [Table 11]

[0416] 4. Experimental Conclusion: The compounds of the examples shown in the present invention were able to effectively reduce LDL-C in a B6-hPCSK9 transgenic mouse animal model of hyperlipidemia.

Claims

1. A compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Ring A is, 【Chemistry 2】 Selected from, Ring B is C ３－１２ Cycloalkyl group, 3-12 membered heterocyclyl group, C ６－１４ Selected from an aryl group or a 5- to 14-membered heteroaryl group, L １ is a bond, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ C(O)NR ａａ (CH ２ ) ｎ１ -, -(CH ２ ) ｎ (CR ａａ R ｂｂ ) ｎ２ -, -(CR ａａ R ｂｂ ) ｎ O(CH ２ ) ｎ１ -, -(CH ２ ) ｎ O(CR ａａ R ｂｂ ) ｎ１ -, -(CR ａａ R ｂｂ ) ｎ３ S(CH ２ ) ｎ４ -, -(CH ２ ) ｎ S(CR ａａ R ｂｂ ) ｎ３ -, -(CR ａａ R ｂｂ ) ｎ３ (CH ２ ) ｎ NR ｃｃ -, -(CH ２ ) ｎ NR ａａ (CR ｂｂ R ｃｃ ) ｎ -, -(CH<00000​​​​​​​​​​​​​​​​​​​​​​​ ａａ R ｂｂ -, - (CH ２ ) ｎ NR ｃｃ C(O)R ｄｄ -, - (CH ２ ) ｎ S(O) ｍ NR ａａ R ｂｂ - and - (CH ２ ) ｎ NR ｃｃ S(O) ｍ R ｄｄ - Selected from, R ａａ , R ｂｂ、 R ｃｃ and R ｄｄ Each of these groups is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent substituents may bond to form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group may be optionally further substituted. Preferably, L １ The bond is selected from -C(O)- or -C(O)NH-, R ａ [R is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ａ１ , -(CH ２ ) ｎ OR Ａ１ , -(CH ２ ) ｎ C(O)R Ａ１ , -(CH ２ ) ｎ C(O)OR Ａ１ , -(CH ２ ) ｎ S(O) ｍ R Ａ１ , -(CH ２ ) ｎ NR Ａ２ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ , -(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ , -(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ )(CH ｎ )(CH ２ )(CH ｎ１ ) Ａ３ R Ａ３ or -(CH ２ ) ｎ [[ID=Io0]]NR[[ID=Io1]] Ａ２ [[ID=Io2]]S(O)[[ID=Io3]] ｍ [[ID=Io4]]R Ａ３ The amino group, alkyl group, alkenyl group, alkynyl group, alkylthio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R Ａ１ ~R Ａ３ Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent R ａ These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R ｂ This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｂ１ ,-(CH ２ ) ｎ OR Ｂ１ ,-(CH ２ ) ｎ C(O)R Ｂ１ ,-(CH ２ ) ｎ C(O)OR Ｂ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｂ１ ,-(CH ２ ) ｎ NR Ｂ２ R Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)OR Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)(CH ２ ) ｎ１ R Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)NR Ｂ２ R Ｂ３ ,-(CH ２ ) ｎ C(O)NR Ｂ２ (CH ２ ) ｎ１ R Ｂ３ , -OC(R Ｂ１ R Ｂ２ ) ｎ (CH ２ ) ｎ１ R Ｂ３ or - (CH ２ ) ｎ NR Ｂ２ S(O) ｍ R Ｂ３ The amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R Ｂ１ ~R Ｂ３ Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent R ｂ These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R ｃ This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｃ１ ,-(CH ２ ) ｎ OR Ｃ１ ,-(CH ２ ) ｎ C(O)R Ｃ１ ,-(CH ２ ) ｎ C(O)OR Ｃ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｃ１ ,-(CH ２ ) ｎ NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or - (CH ２ ) ｎ NR Ｃ２ S(O) ｍ R Ｃ３ The amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R Ｃ１ ~R Ｃ３ Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent R ｃ These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R ｄ This includes hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, oxo group, thio group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ R Ｄ１ ,-(CH ２ ) ｎ OR Ｄ１ ,-(CH ２ ) ｎ C(O)R Ｄ１ ,-(CH ２ ) ｎ C(O)OR Ｄ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｄ１ ,-(CH ２ ) ｎ NR Ｄ２ R Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ ,-(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or - (CH ２ ) ｎ NR Ｄ２ S(O) ｍ R Ｄ３ The amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, alkyl group substituted with a cyano group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. R Ｄ１ ~R Ｄ３ Each of these groups is independently selected from hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Alternatively, any two adjacent or non-adjacent R ｄ These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. Or, any two R ｃ and R ｄ These groups bond to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may be further optionally substituted. x is 0, 1, 2, or 3. y is 0, 1, 2, or 3. z is 0, 1, 2, or 3. e is 0, 1, 2, or 3. m is 0, 1, or 2. n is 0, 1, 2, 3, or 4. n1 is 0, 1, 2, 3, or 4. n2 is 0, 1, 2, 3, or 4. n3 is 0, 1, 2, 3 or 4. n4 is 0, 1, 2, 3, or 4, and the compound shown in general formula (I), its stereoisomer, or its pharmaceutically acceptable salt.

2. The compound is further represented by the general formula (I-A), 【Transformation 3】 Here, Ring B is C ３－６ Selected from cycloalkyl groups, phenyl groups, 5-membered nitrogen-containing heterocyclyl groups, 6-membered nitrogen-containing heterocyclyl groups, 5-membered nitrogen-containing heteroaryl groups, 6-membered nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heterocyclyl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heterocyclyl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heterocyclyl groups, or 6-membered condensed 6-membered bicyclic nitrogen-containing cycloaryl groups. R ｃ－１ These are halogens, amino groups, hydroxyl groups, cyano groups, nitro groups, and C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｃ１ ,-(CH ２ ) ｎ OR Ｃ１ ,-(CH ２ ) ｎ C(O)R Ｃ１ ,-(CH ２ ) ｎ C(O)OR Ｃ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｃ１ ,-(CH ２ ) ｎ NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or - (CH ２ ) ｎ NR Ｃ２ S(O) ｍ R Ｃ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. R Ｃ１ ~R Ｃ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｃ－１ -F, -Cl, -O-CH ３ -CN, -CF ３ ien-CH ３ , -O-CF ３ , -O-CH ３ , -O-CH(CH ３ ) ２ , 【Chemistry 4】 Selected from, R ｃ－２ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｃ１ ,-(CH ２ ) ｎ OR Ｃ１ ,-(CH ２ ) ｎ C(O)R Ｃ１ ,-(CH ２ ) ｎ C(O)OR Ｃ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｃ１ ,-(CH ２ ) ｎ NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or - (CH ２ ) ｎ NR Ｃ２ S(O) ｍ R Ｃ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. R Ｃ１ ~R Ｃ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｃ－２ -H, -F, -Cl, -O-CH ３ -CN, -CF ３ ien-CH ３ , -O-CF ３ , -O-CH ３ , -O-CH(CH ３ ) ２ , 【Transformation 5】 Selected from, R ｃ－３ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｃ１ ,-(CH ２ ) ｎ OR Ｃ１ ,-(CH ２ ) ｎ C(O)R Ｃ１ ,-(CH ２ ) ｎ C(O)OR Ｃ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｃ１ ,-(CH ２ ) ｎ NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or - (CH ２ ) ｎ NR Ｃ２ S(O) ｍ R Ｃ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. R Ｃ１ ~R Ｃ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｃ－３ -H, -F, -Cl, -O-CH ３ -CN, -CF ３ , -CD ３ ien-CH ３ , -O-CF ３ , -O-CH ３ , -O-CH(CH ３ ) ２ , 【Transformation 6】 Selected from, More specifically, R ｃ－３ -H, -F, -Cl, -O-CH ３ -CN, -CF ３ ien-CH ３ , -O-CF ３ , -O-CH ３ , -O-CH(CH ３ ) ２ , 【Transformation 7】 Selected from, m is 0, 1, or 2. n is 0, 1, 2, 3, or 4. The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n1 is 0, 1, 2, 3, or 4.

3. The compound is further represented by the general formula (I-A-1). 【Transformation 8】 A compound according to feature 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. The compound is further represented by the general formula (I-2'), 【Chemistry 9】 Here, L １ These are bonds, -C(O)-, -C(O)NH-, and -C(O)NCH ３ - or -C(O)N(CH ３ ) ２ Selected from, M ５ is N or CR ５ Selected from, R ５ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, Halo C １－６ Alkoxy group, C １－６ C substituted with hydroxyalkyl groups and cyano groups １－６ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Selected from aryl groups and 5- to 14-membered heteroaryl groups, the amino group, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, Halo C １－６ Alkoxy group, C １－６ C substituted with hydroxyalkyl groups and cyano groups １－６ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ The aryl group and the 5-14 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, which may be further substituted with one or more substituents from among an aryl group and a 5- to 10-membered heteroaryl group.

5. The compound is further represented by the general formula (I-1-a), 【Chemistry 10】 More preferably, 【Chemistry 11】 And, Here, R ａ－１ ~R ａ－４ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, oxo group, thio group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, Halo C １－６ Alkoxy group, C １－６ C substituted with hydroxyalkyl groups and cyano groups １－６ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ Aryl group, 5-14 membered heteroaryl group, -(CH ２ ) ｎ R Ａ１ ,-(CH ２ ) ｎ OR Ａ１ ,-(CH ２ ) ｎ C(O)R Ａ１ ,-(CH ２ ) ｎ C(O)OR Ａ１ ,-(CH ２ ) ｎ S(O) ｍ R Ａ１ ,-(CH ２ ) ｎ NR Ａ２ R Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ ,-(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or - (CH ２ ) ｎ NR Ａ２ S(O) ｍ R Ａ３ Selected from the above, the amino group, C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylthio group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, Halo C １－６ Alkoxy group, C １－６ C substituted with hydroxyalkyl groups and cyano groups １－６ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１２ The aryl group and the 5-14 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 10-membered heteroaryl group. R Ａ１ ~R Ａ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ Selected from an aryl group or a 5- to 14-membered heteroaryl group, the amino group, C １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ The aryl group and the 5-14 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Haloalkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl group, 3-12 member heterocyclyl group, C ６－１４ They may be further substituted with one or more substituents from an aryl group and a 5- to 14-membered heteroaryl group. m is 0, 1, or 2. n is 0, 1, 2, 3 or 4, and The compound according to any one of claims 1 to 4, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that n1 is 0, 1, 2, 3, or 4.

6. Ring B is C ３－６ Selected from cycloalkyl groups, phenyl groups, 3-8 membered heterocyclyl groups, 7-10 membered bicyclic heterocyclyl groups, 5 membered heteroaryl groups, 6 membered heteroaryl groups, 5 membered condensed 5 membered bicyclic heteroaryl groups, 5 membered condensed 6 membered bicyclic heteroaryl groups, 6 membered condensed 5 membered bicyclic heteroaryl groups, or 6 membered condensed 6 membered bicyclic heteroaryl groups. More preferably, ring B is C ３－６ Selected from cycloalkyl groups, phenyl groups, 5-membered nitrogen-containing heterocyclyl groups, 6-membered nitrogen-containing heterocyclyl groups, 7-10-membered bicyclic heterocyclyl groups, 5-membered nitrogen-containing heteroaryl groups, 6-membered nitrogen-containing heteroaryl groups, 5-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, 5-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups, 6-membered condensed 5-membered bicyclic nitrogen-containing heteroaryl groups, or 6-membered condensed 6-membered bicyclic nitrogen-containing heteroaryl groups. More preferably, ring B is selected from pyridine, pyrimidine, pyridone, or pyrimidone. More preferably, ring B is pyridine, pyrimidine, benzene, 【Chemistry 12】 A compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among the above.

7. R ａ is hydrogen, deuterium, halogen, amino group, hydroxy group, cyano group, nitro group, C １－３ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, oxo group, thio group, C １－３ alkylthio group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ alkoxy group, halo C １－３ alkoxy group, C １－３ hydroxyalkyl group, C substituted with cyano group １－３ alkyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group, 5- to 12-membered heteroaryl group, -(CH ２ ) ｎ R Ａ１ ,-(CH ２ ) ｎ OR Ａ１ ,-(CH ２ ) ｎ C(O)R[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or -(CH ２ ) ｎ NR Ａ２ S(O) ｍ R Ａ３ selected from, the amino group, C １－３ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－３ alkylthio group, C<00********>deuterated alkyl group, C １－３ haloalkyl group, C １－３ [[ID=3********]]alkoxy group, haloC １－３ alkoxy group, C １－３ hydroxyalkyl group, C substituted with a cyano group １－３ alkyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to l2-membered heteroaryl group may optionally be further substituted, and optionally, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ haloalkyl group, C １－３ hydroxyalkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group, C １－３ haloalkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and one or more substituents selected from 5- to 10-membered heteroaryl groups may be further substituted, the amino group, C １－３ alkyl group, C ２－４ alkenyl group, C ２－４ [[ID=7********]]alkynyl group, C １－３ deuterated alkyl group, C １－３ [[ID=************]]haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 10-membered heteroaryl group. R Ａ１ ~R Ａ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ａ は、-H、-O-CHF ２ 、-O-CF ３ 、-O-CF ２ Cl、-O-CF ２ Br、-O-CH ２ -CHF ２ 、-O-CH ２ -CF ３ -CHF ２ 、-CF ３ 、-CH ２ -OH、-CH ２ -CHF ２ 、-CH(CH ３ )-OH、-(CH ２ ) ３ -OH、-C(CH ３ ) ２ -OH、-OH、-O-CH ３ 、-CH ３ 、-CF ３ 、-F、-Cl、-CN、-NHCH ３ 、-NH ２ 、 【Chemistry 13】 Selected from, and / or, R ｃ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｃ１ ,-(CH ２ ) ｎ OR Ｃ１ ,-(CH ２ ) ｎ C(O)R Ｃ１ ,-(CH ２ ) ｎ C(O)OR Ｃ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｃ１ ,-(CH ２ ) ｎ NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)OR Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)(CH ２ ) ｎ１ R Ｃ３ ,-(CH ２ ) ｎ NR Ｃ２ C(O)NR Ｃ２ R Ｃ３ ,-(CH ２ ) ｎ C(O)NR Ｃ２ (CH ２ ) ｎ１ R Ｃ３ , -OC(R Ｃ１ R Ｃ２ ) ｎ (CH ２ ) ｎ１ R Ｃ３ or - (CH ２ ) ｎ NR Ｃ２ S(O) ｍ R Ｃ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. R Ｃ１ ~R Ｃ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｃ -H, -F, -Cl, -O-CH ３ -CN, -CF ３ ien-CH ３ , -O-CF ３ , -O-CH ３ , -O-CH(CH ３ ) ２ , 【Chemistry 14】 A compound according to any one of claims 1 to 4 or 6, characterized by being selected from, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. R ｂ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｂ１ ,-(CH ２ ) ｎ OR Ｂ１ ,-(CH ２ ) ｎ C(O)R Ｂ１ ,-(CH ２ ) ｎ C(O)OR Ｂ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｂ１ ,-(CH ２ ) ｎ NR Ｂ２ R Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)OR Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)(CH ２ ) ｎ１ R Ｂ３ ,-(CH ２ ) ｎ NR Ｂ２ C(O)NR Ｂ２ R Ｂ３ ,-(CH ２ ) ｎ C(O)NR Ｂ２ (CH ２ ) ｎ１ R Ｂ３ , -OC(R Ｂ１ R Ｂ２ ) ｎ (CH ２ ) ｎ１ R Ｂ３ or - (CH ２ ) ｎ NR Ｂ２ S(O) ｍ R Ｂ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. R Ｂ１ ~R Ｂ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｂ This is selected from -H or -F. and / or R ｄ These are hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ｄ１ ,-(CH ２ ) ｎ OR Ｄ１ ,-(CH ２ ) ｎ C(O)R Ｄ１ ,-(CH ２ ) ｎ C(O)OR Ｄ１ ,-(CH ２ ) ｎ S(O) ｍ R Ｄ１ ,-(CH ２ ) ｎ NR Ｄ２ R Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)OR Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)(CH ２ ) ｎ１ R Ｄ３ ,-(CH ２ ) ｎ NR Ｄ２ C(O)NR Ｄ２ R Ｄ３ ,-(CH ２ ) ｎ C(O)NR Ｄ２ (CH ２ ) ｎ１ R Ｄ３ , -OC(R Ｄ１ R Ｄ２ ) ｎ (CH ２ ) ｎ１ R Ｄ３ or - (CH ２ ) ｎ NR Ｄ２ S(O) ｍ R Ｄ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 10-membered heteroaryl group. R Ｄ１ ~R Ｄ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ｄ は、-H、-D、-F、-Cl、-CN、-CH ３ 、-CF ３ 、-CH(CH ３ ) ２ 、-C(CH ３ ) ３ 、-C(CH ３ ) ２ -OH、-C(CH ３ ) ２ -CH ２ -OH、-O-CH ３ 、-CH ２ -NH ２ 、-CH ２ -OH、-NH ２ 、-OH、 【Chemistry 15】 A compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among the above.

9. R ａ－１ ~R ａ－４ These are, independently, hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, and C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, oxo group, thio group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Aryl group, 5-12 membered heteroaryl group, -(CH ２ ) ｎ R Ａ１ ,-(CH ２ ) ｎ OR Ａ１ ,-(CH ２ ) ｎ C(O)R Ａ１ ,-(CH ２ ) ｎ C(O)OR Ａ１ ,-(CH ２ ) ｎ S(O) ｍ R Ａ１ ,-(CH ２ ) ｎ NR Ａ２ R Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)OR Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)(CH ２ ) ｎ１ R Ａ３ ,-(CH ２ ) ｎ NR Ａ２ C(O)NR Ａ２ R Ａ３ ,-(CH ２ ) ｎ C(O)NR Ａ２ (CH ２ ) ｎ１ R Ａ３ , -OC(R Ａ１ R Ａ２ ) ｎ (CH ２ ) ｎ１ R Ａ３ or - (CH ２ ) ｎ NR Ａ２ S(O) ｍ R Ａ３ Selected from the above, the amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylthio group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ C substituted with hydroxyalkyl groups and cyano groups １－３ alkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group may be further optionally substituted with deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The amino group, C １－３ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, Halo C １－３ Alkoxy group, C １－３ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 10-membered heteroaryl group. R Ａ１ ~R Ａ３ These are, independently, hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ Selected from an aryl group or a 5- to 12-membered heteroaryl group, the amino group, C １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Haloalkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl group and the 5-12 membered heteroaryl group can be optionally composed of deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, and C. １－３ alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Haloalkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The group may be further substituted with one or more substituents from an aryl group and a 5- to 12-membered heteroaryl group. Preferably, R ａ－１ ~R ａ－４ These are, independently, -H and -O-CHF. ２ , -O-CF ３ , -O-CF ２ Cl, -O-CF ２ Br, -O-CH ２ - CHF ２ , -O-CH ２ -CF ３ ,-CHF ２ , -CF ３ ien-CH ２ -OH, -CH ２ - CHF ２ , -CH(CH ３ )-OH,-(CH ２ ) ３ -OH, -C(CH ３ ) ２ -OH, -OH, -O-CH ３ ien-CH ３ , -CF ３ , -F, -Cl, -CN, -NHCH ３ , -NH ２ ien-CH ２ -CF ３ , 【Chemistry 16】 A compound according to claim 5 or 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 10】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 A compound of general formula (I) according to any one of claims 1 to 9, characterized by being selected from the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A compound represented by general formula (IV), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 25】 X ２ These are an amino group, a nitro group, a halogen, boric acid, or a boric acid ester. A compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the other groups is as described in claim 2. 【Request Item 12】 【Chemistry 26】 A compound of general formula (IV) according to claim 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the compounds.

13. A method for producing a compound represented by the general formula (I-A) described in claim 2, comprising the following steps: 【Chemistry 27】 Here, X ３ These are a hydroxyl group, an amino group, a methylthio group, a halogen, a boric acid, or a boric acid ester. General formula compound (IV) and general formula compound (IV-1) are reacted to obtain general formula compound (I-A), A method characterized in that each of the other groups is as described in claim 2.

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

15. Application of a compound of general formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a PCSK9 inhibitor drug.

16. Application of a compound of general formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of an LDL-reducing drug.

17. An application of a compound of general formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a drug for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or symptoms thereof, preferably an application in the manufacture of a drug for stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal lipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

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