A class of nitrogen-containing heterocyclic derivative inhibitors, their preparation methods and applications

Abstract

This invention relates to a class of nitrogen-containing heterocyclic derivative inhibitors, their preparation methods, and applications. In particular, this invention relates to compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as inhibitors in the treatment of cardiovascular and cerebrovascular diseases, wherein the substituents in general formula (I) are the same as defined in the specification.

Description

[0001] This application claims the following priority:

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

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

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

[0005] CN202311552677.1, application date November 17, 2023;

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

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

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

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

[0010] This invention belongs to the field of drug synthesis, specifically relating to a class of nitrogen-containing heterocyclic derivative inhibitors, their preparation methods, and applications. Background Technology

[0011] Cardiovascular disease (CVD) is a leading cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C on the arterial walls leads to atherosclerosis and can trigger inflammatory responses, resulting in cardiovascular events such as heart attacks and strokes. Although statins can lower serum LDL-C and are currently the main lipid-lowering drugs in clinical practice, patients who are intolerant to statins or who fail to reach their treatment goals when receiving tolerated doses still face risks, such as patients with familial hypercholesterolemia. The discovery of PCSK9 inhibitors provides a more aggressive treatment option for homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when used in combination with statins, can lower LDL-C by 15%-20%, while PCSK9 inhibitors combined with statins can significantly lower LDL-C by 54%-74%. PCSK9 inhibitors can also overcome the intolerable side effects of statins, such as muscle pain.

[0012] PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease highly expressed in the liver. Loss-of-function mutations in the PCSK9 gene are associated with low LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), and it has been clinically validated as a therapeutic target for hyperlipidemia. PCSK9 is synthesized as an enzyme precursor, and after synthesis, it undergoes autocatalytic cleavage within the cell. The propeptide binds to mature PCSK9 and is secreted extracellularly, thus blocking the catalytic activity of PCSK9.

[0013] PCSK9 is a major regulator of low-density lipoprotein receptor (LDLR) levels on the surface of hepatocytes and can inhibit the LDLR circulation pathway. LDLR function is crucial for maintaining cholesterol homeostasis, responsible for the uptake and degradation of low-density lipoprotein. Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100. The LDL / LDLR complex is internalized through receptor-mediated endocytosis. The low intracellular pH environment causes LDLR to release LDL, which then circulates back to the cell membrane. Intracellular free LDL is transported to lysosomes and degraded. Secreted PCSK9 interferes with LDLR circulation by binding to LDLR on the hepatocyte surface. After the PCSK9 / LDLR complex migrates through clathrin-encapsulated pits into the acidic endosomal chamber, a conformational change in LDLR leads to the formation of additional binding sites with PCSK9. Therefore, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR circulation and thus upregulating LDL-C levels.

[0014] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein cholesterol metabolism, affecting 1 in 250 people, characterized by significantly elevated LDL-C levels. Heterozygous FH patients have a 3-4 times higher risk of developing coronary artery disease (CAD) and often develop CAD an average of 10 years earlier than the general population. Statins lower LDL-C in heterozygous FH patients; in Besselin's study, high-intensity statin therapy was shown to reduce CAD risk and mortality by 44%. However, in many cases, the reduction in LDL-C is considered insufficient. The complementarity mechanism of statins involves upregulating sterol regulatory element-binding protein 2 (SREBP-2), thereby activating LDL receptors and PCSK9, increasing PCSK9 expression and secretion binding to LDLR, leading to elevated LDL-C levels in the blood. Therefore, while statins lower LDL by inhibiting HMGCoA, they counteract the effects of SREBP; adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatments such as PCSK9 inhibitors are needed.

[0015] PCSK9 macromolecule inhibitors, such as the monoclonal antibody-based drugs Alirocumab and Evolocumab, selectively bind to extracellular PCSK9 and prevent its interaction with LDLR. They have been approved by the FDA for lowering LDL-C levels with a good safety profile. Studies have shown that in heterozygous FH patients who have not reached their LDL-C target after statin monotherapy, once-every-two-week injections of Alirocumab maximally reduce cardiovascular risk. Alirocumab has also shown a moderate increase in "good" cholesterol (HDL-C). Additionally, the PCSK9 siRNA drug Inclisiran is currently marketed; it lowers PCSK9 protein expression levels for long-term lipid reduction with a good safety profile. However, both of these drugs require injection and are expensive to produce. Currently, there are no marketed PCSK9 small molecule inhibitors, therefore there is a high demand for oral PCSK9 small molecule inhibitors.

[0016] There are already patent reports on PCSK9 small molecule inhibitors, such as WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ), and WO2022133529 (Nyrada). Currently, AZD-0780 is the most advanced in Phase I clinical trials, while the others are in preclinical development. Several peptides have also been reported, with the most advanced being in Phase II clinical trials. This invention aims to develop an orally administered PCSK9 small molecule inhibitor. Summary of the Invention

[0017] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of general formula (I) has the following structure:

[0018]

[0019] Wherein: ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl;

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

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

[0022] R aa 、R bb、 R cc 和R ddEach of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0023] Alternatively, any two adjacent or non-adjacent substituents may be linked to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, which may optionally be further substituted.

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

[0025] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, alkathio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) 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 RA3 Or -(CH2) n NR A2 S(O) m R A3 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

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

[0027] Preferably, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2)n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0028] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0029] Or, any two adjacent or non-adjacent R a The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0030] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

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

[0032] Preferably, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 RB3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0033] R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0034] Or, any two adjacent or non-adjacent R b The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0035] Preferably, or, any two R a and R b The linkage forms a heterocyclic or heteroaryl group, which may optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0036] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0037] R C1 ~R C3Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0038] Preferably, R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n(CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0039] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0040] Or, any two adjacent or non-adjacent R c The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0041] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3-(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0042] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0043] Preferably, R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1-(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0044] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0045] Or, any two adjacent or non-adjacent R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0046] Or, any two R c and R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

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

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

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

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

[0051] In a preferred embodiment of the invention, the compound is further shown as in general formula (IA):

[0052]

[0053] Wherein: Ring A is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12-membered heteroaryl; preferably from 5-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl;

[0054] Ring B is selected from C 3-8 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl or 5-12 heteroaryl; preferably from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl, 6-membered 6-membered bicyclic nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered 5-membered bicyclic nitrogen-containing heterocyclic group or 6-membered 6-membered bicyclic nitrogen-containing cyclic aryl;

[0055] R c-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2(CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0056] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-12 heteroaryl groups; preferably, R c-1 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0057] Or, R c-1 Preferred from halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2)n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0058] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0059] Preferably, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0060] More preferably, Rc-1 Selected from -F;

[0061] R c-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0062] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0063] Preferably, R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0064] R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3-(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0065] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0066] Preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0067] More preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0068] m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; n1 is 0, 1, 2, 3, or 4;

[0069] Other groups are defined as described above.

[0070] In a preferred embodiment of the invention, the compound is further shown as of general formula (IA-1):

[0071]

[0072] The functional groups are defined as described above.

[0073] In a more preferred embodiment of the present invention, the ring A is selected from 5-membered monoheteroaryl, 5-membered 5-membered bicyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered monoheteroaryl, 6-membered 5-membered bicyclic heteroaryl or 6-membered 6-membered bicyclic heteroaryl.

[0074] Further optimization

[0075] In a preferred embodiment of the invention, the compound is further shown as in general formula (I-2'):

[0076]

[0077] L1 is selected from bond, -C(O)-, -C(O)NH-, -C(O)NCH3- or -C(O)N(CH3)2; M5 is selected from N or CR5;

[0078] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 membered heteroaryl, said amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents of aryl and 5-10 heteroaryl groups; other groups are defined as described above.

[0079] In a preferred embodiment of the invention, the compound is further shown as in general formula (I-1-a):

[0080]

[0081] Where: R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2)n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0082] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0083] Other groups are defined as described above;

[0084] m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and n1 is 0, 1, 2, 3, or 4.

[0085] In a preferred embodiment of the invention, the compound is further shown as of general formula (I-1-a'):

[0086]

[0087] The functional groups are defined as described above.

[0088] In a more preferred embodiment of the present invention, the ring B is selected from C. 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic, 7-10 membered bicyclic heterocyclic, 5 membered heteroaryl, 6 membered heteroaryl, 5 membered 5 membered bicyclic heteroaryl, 5 membered 6 membered bicyclic heteroaryl, 6 membered 5 membered bicyclic heteroaryl or 6 membered 6 membered bicyclic heteroaryl;

[0089] More preferably, ring B is selected from C. 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic heterocyclic group, 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl;

[0090] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0091] More preferably, ring B is selected from pyridine, pyrimidine, pyridinone, or pyrimidinone;

[0092] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0093] In a further preferred embodiment of the present invention, the R described herein a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0094] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C.1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

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

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

[0097] More preferably, R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3-CHF2, -CF3, -CH2-OH, -CH2- CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2,

[0098] In a further preferred embodiment of the present invention, the R described herein a-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NRA2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0099] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0100] Preferably, R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0101] More preferably, R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0102] In a further preferred embodiment of the present invention, the R described herein a-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0103] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0104] Preferably, R a-2 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0105] More preferably, R a-2Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0106] In a further preferred embodiment of the present invention, the R described herein a-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NRA2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0107] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0108] Preferably, R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0109] More preferably, R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0110] In a further preferred embodiment of the present invention, the R described herein a-4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) mR A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0111] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0112] Preferably, R a-4 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0113] More preferably, R a-4 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0114] In a further preferred embodiment of the present invention, the R described herein b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0115] R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0116] Preferably, R b Choose from -H or -F.

[0117] In a further preferred embodiment of the present invention, any two Rs described in the present invention b Linked with adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl compounds.

[0118] In a further preferred embodiment of the present invention, the R described herein a and R b The linker forms a 5-12 membered heterocyclic group or a 5-12 heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 heteroaryl group may optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0119] In a further preferred embodiment of the present invention, the R described herein c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n RC1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0120] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0121] Preferably, R cSelected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0122] More preferably, R c Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0123] In a further preferred embodiment of the present invention, the R described herein d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2(CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0124] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0125] Preferably, R dSelected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CD3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0126] More preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0127] More preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH,

[0128] In a further preferred embodiment of the invention, the compound contains Preferred from

[0129] In a further preferred embodiment of the invention, the compound contains Selected from Where R c-1 R c-2 and R c-3 The definition is the same as R c Preferably, R c-1 R c-2 and R c-3 The definition of R is as described above. c-1 R c-2 and R c-3 Definition.

[0130] The present invention further provides compounds of general formula (IV), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0131]

[0132] Wherein: X2 is amino, nitro, halogen, boric acid or borate ester; other groups are as described above;

[0133] Preferably, the compound represented by general formula (IV) is further represented as (IV-A), (IV-B), or (IV-C):

[0134]

[0135] In a further preferred embodiment of the invention, the compound of general formula (IV), its stereoisomers, or pharmaceutically acceptable salts thereof are characterized by being selected from the following compounds:

[0136]

[0137] The present invention further provides a method for producing a compound of general formula (IA), comprising the following steps:

[0138]

[0139] Wherein: X3 is hydroxyl, amino, halogen, boric acid or borate ester;

[0140] The reaction of compound (IV) with compound (IV-1) yields compound (IA);

[0141] The other groups are as described above;

[0142] Preferably, the compound represented by the general formula (IA) is further represented as (IA-1), (I-1-a), or (I-1-a'):

[0143]

[0144] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0145] The present invention further relates to any of the compounds of general formula (I) shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical compositions thereof in the preparation of PCSK9 inhibitor medicaments.

[0146] The present invention further relates to any of the compounds of general formula (I) shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition thereof in the preparation of an LDL-lowering drug; preferably, the LDL is LDL-C.

[0147] The present invention further relates to the use of compounds of general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or their symptoms; preferably, in the preparation of medicaments for stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0148] The present invention further relates to the use of compounds of general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of methods for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or their symptoms, preferably in the preparation of methods for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0149] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, comprising administering to a patient a therapeutically effective dose of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0150] Further, the compound, its stereoisomer, or its pharmaceutically acceptable salt constitutes 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15-40%, even more preferably 20-30%, and even more preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0151] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to PCSK9.

[0152] The present invention also relates to methods for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in mammals, comprising administering to said mammals a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0153] Detailed description of the invention

[0154] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0155] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain 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, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0156] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0157] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexenediyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0158] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0159] wait;

[0160] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0161] wait.

[0162] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0163] wait.

[0164] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0165]

[0166] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0167] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups; or, preferably, it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, further preferably, it contains 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclic groups containing 1 to 3 nitrogen and / or oxygen atoms.

[0168] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0169] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0170] wait.

[0171] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O).m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, they are 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered and 5-membered or 5-membered and 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0172] wait.

[0173] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0174] wait.

[0175] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0176] wait.

[0177] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0178] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0179] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0180] wait.

[0181] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0182] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered monocyclic heteroaryl or 8-12-membered bicyclic heteroaryl, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, pyridazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl.

[0183] The bicyclic heteroaryl group is preferably a 5-membered 5-membered bicyclic heteroaryl group, a 5-membered 6-membered bicyclic heteroaryl group, a 6-membered 5-membered bicyclic heteroaryl group, or a 6-membered 6-membered bicyclic heteroaryl group. Non-limiting examples include:

[0184]

[0185] The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0186] wait.

[0187] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo, or carboxylic acid ester group.

[0188] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0189] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0190] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0191] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0192] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0193] "Alkyne" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0194] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0195] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0196] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0197] In the compounds described in this invention, the enol and lactam structures are tautomers, and those skilled in the art should know that they are the same molecule. They are the same molecule.

[0198] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0199] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0200] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0201] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0202] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0203] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0204] Example

[0205] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer in the following solvents: deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O), with tetramethylsilane (TMS) as the internal standard (if applicable).

[0206] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0207] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0208] The compounds of this invention have significant advantages in terms of drug properties such as solubility, permeability, and safety.

[0209] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0210] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0211] The eluent system for silica gel column chromatography and the developing solvent system for thin-layer chromatography used in the intermediates and the purification compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0212] Unless otherwise specified, in the embodiments of the present invention, the ratio of the mobile phase in the HPLC chiral separation condition and the HPLC chiral analysis condition is a volume ratio.

[0213] Intermediate 1

[0214] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0215]

[0216] Intermediate 1 was synthesized by referring to the preparation method of patent WO2020150473A2.

[0217] MS m / z (ESI): 245.1 [M+H] + .

[0218] Intermediate 1 can also be obtained in the following ways:

[0219]

[0220] Step 1: 2-Chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated sodium chloride solution (50 mL). The mixture was dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to obtain (1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentylcarbamate tert-butyl ester 1B (2.1 g), yield: 55.1%. MS m / z (ESI): 345.2 [M+H] + .

[0221] Step 2: Dissolve 1B (2.1 g, 6.1 mmol) in methanol (10 mL), add dioxane solution of hydrochloric acid (4 M, 20 mL), and stir the reaction at room temperature for 2 hours. Concentrate the reaction solution, add ammonia methanol solution (7 M, 10 mL) to adjust the pH to weakly alkaline, concentrate again, and purify the residue by silica gel chromatography (elution system A) to obtain (1S,3S)-N. 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g), yield: 87.3%. MS m / z (ESI): 245.1 [M+H] + .

[0222] Intermediate 2

[0223] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0224]

[0225] Step 1: 2-Fluoro-5-iodopyridine 2A (5 g, 22.4 mmol), 2-hydroxypyridine (2.35 g, 24.7 mmol), cuprous iodide (427 mg, 2.24 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (159 mg, 1.12 mmol), and cesium carbonate (9.5 g, 29.2 mmol) were dissolved in 1,4-dioxane (75 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into 100 mL of water. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 6'-fluoro-2H-[1,3'-bipyridine]-2-one 2B (3.1 g), yield: 72.7%. MS m / z (ESI): 191.1 [M+H] + .

[0226] Step 2: (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (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). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 2C (2.9 g) of ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamate tert-butyl ester, yield: 78.4%. MS m / z (ESI): 371.2 [M+H] + .

[0227] Step 3: 2.9 g (7.83 mmol) of tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)aminocarbamate 2C was dissolved in 30 mL of 4 M dioxane hydrochloride solution, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reversed-phase chromatography (eluting system C) to give intermediate 2 (1.5 g) of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 70.9%. MS m / z (ESI): 271.2 [M+H] + .

[0228] Reference Example 1

[0229] 6'-((3-(((1S,3S)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0230]

[0231] Step 1: 7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-amine (Reference Example 1a, 100 mg, 0.657 mmol) was dissolved in acetonitrile under ice bath conditions with stirring. Sodium nitrite (91 mg, 1.31 mmol) was added to the reaction solution, and stirring was continued for 1 minute. Hydrochloric acid (4 M, 0.41 mL) was added dropwise to the reaction solution, and the reaction was heated to room temperature with stirring. The reaction was detected as complete using a thin-layer chromatography plate. Saturated sodium bicarbonate solution was added dropwise to the reaction solution until pH = 7. The reaction solution was extracted with dichloromethane (10 mL × 3), the organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 2-chloro-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (Reference Example 1b, 65 mg), yield: 77.5%. MS m / z (ESI): 172.1 [M+H] + .

[0232] Step 2: Under nitrogen protection, dissolve 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) in 1,4-dioxane (2 mL). Heat the reaction solution to 130 °C and microwave for 2 hours. Then heat the reaction solution to 130 °C under nitrogen protection and react for 16 hours. Filter and concentrate the reaction solution. The residue was subjected to preparative HPLC (alkaline system) to give 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (Reference Example 1, 6.6 mg), yield 4.08%. MS m / z (ESI): 406.2 [M+H] + .

[0233] 1 H NMR(400MHz,DMSO-d6)δ8.69–6.59(m,1H),7.92(d,1H),7.60(dd,1H),7.51–7.35(m,2H),7.27(dd,1H),6.97–6.82(m,2H),6.74(d,1H) ,6.52(d,1H),6.44(d,1H),6.26(t,1H),4.35–4.28(m,1H),4.20–4.10(m,1H),2.20–2.07(m,2H),2.00–1.82(m,2H),1.60–1.42(m,2H).

[0234] See Example 2

[0235] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0236]

[0237] Step 1: Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (Reference Example 2a) (500 mg, 2.31 mmol), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (510 mg, 2.55 mmol), cesium carbonate (1.51 g, 4.63 mmol), tris(dibenzylacetone)dipalladium (424 mg, 0.46 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL), and the mixture was microwaved to 130 °C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (elution system B) and preparative HPLC (formic acid system) to give N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate tert-butyl (Reference Example 2b, 240 mg), yield: 30.9%. MS m / z (ESI): 336.0 [M+H] + .

[0238] 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 hydrochloric acid (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 (ammonia system) to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 2c) (140 mg), yield: 98.6%. MS m / z (ESI): 236.2 [M+H] + .

[0239] Step 3: Reference Example 2c (150 mg, 0.64 mmol), 2-fluoro-5-nitro-pyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N3-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 2d, 190 mg), yield: 83.4%. MS m / z (ESI): 358.1 [M+H] + .

[0240] Step 4: In a hydrogen atmosphere, at room temperature, dissolve Reference Example 2d (190 mg, 0.53 mmol) and palladium on carbon (28 mg, 0.026 mmol, purity: 10%) in methanol (5 mL) and stir for 1 hour. Filter the reaction solution and concentrate the filtrate to give N2-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine (Reference Example 2e, 170 mg), yield: 97.7%. MS m / z (ESI): 328.1 [M+H] + .

[0241] Step 5: 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) at room temperature and stirred for 1 hour. The mixture was then heated to 50 °C and stirred for 4 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 2, 24.3 mg), yield: 22.4%. MS m / z (ESI): 445.2 [M+H] + .

[0242] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.66(t,1H),8.35(d,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H),7.27(dd,1H),6.86(td,1H),6.75(d ,1H),6.70(d,1H),6.56(d,1H),4.93(s,2H),4.38–4.24(m,1H),4.22– 4.09(m,1H),2.24–2.10(m,2H),2.03–1.82(m,2H),1.66–1.39(m,2H).

[0243] See Example 3

[0244] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0245]

[0246] Following the synthetic method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one was synthesized (Reference Example 3). MS m / z (ESI): 495.2 [M+H] + .

[0247] 1 H NMR(400MHz, DMSO-d6)δ8.83(d,1H),8.75(dd,1H),8.35(d,1H),8.15–8.06(m,1H),7.88(dd,1H),7.86(s,1H),7.62(dd,1H),7.15(dd ,1H),7.04(d,1H),6.71(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).

[0248] Example 3 can also be prepared by the following method:

[0249]

[0250] Step 1: 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and ethyl N-(thiomethylene)carbamate (4.85 g, 37.01 mmol) were dissolved in 1,2-dichloroethane (50 mL) at room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain N-[[4-(trifluoromethyl)-2-pyridyl]carbamate (Reference Example 3a) (9.05 g). The product did not require purification and was used directly in the next step of the reaction. MS m / z (ESI): 294.1 [M+H] + .

[0251] Step 2: 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) at room temperature and stirred for 20 minutes. The mixture was then heated to 65 °C and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine (Reference Example 3b, 5.0 g), yield: 80.60%. MS m / z (ESI): 203.1 [M+H]+ .

[0252] 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 heated to 70 °C and stirred for 2 hours. The reaction solution 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 give 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (Reference Example 3c, 5 g), yield 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0253] Step 4: Under nitrogen protection, 4.5 g (16.92 mmol) of Reference Example 3c, 3.39 g (16.92 mmol) of N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (3.39 g, 16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylacetone)dipalladium (2.32 g, 2.54 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.94 g, 5.07 mmol) were dissolved in 1,4-dioxane (120 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]tert-butyl carbamate (Reference Example 3d, 3.7 g), yield: 56.76%. MS m / z (ESI): 386.2 [M+H] + .

[0254] Step 5: At room temperature, dissolve Reference Example 3d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) in methanol (10 mL) and stir for one hour. Concentrate the reaction solution, dilute the residue with methanol, and adjust the pH to 8-10 with saturated sodium bicarbonate solution. After concentration, purify the residue by silica gel column chromatography (elution system A) to give (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 3e) (2.74 g), yield: 100%. MS m / z (ESI): 286.2 [M+H] + .

[0255] Step 6: Dissolve Reference Example 3e (2.74 g, 9.61 mmol), 2-fluoro-5-nitro-pyridine (1.50 g, 10.57 mmol), and cesium carbonate (7.82 g, 24.01 mmol) in N,N-dimethylformamide (40 mL) and heat to 80 °C with stirring for 16 hours. Filter the reaction mixture and concentrate the filtrate. Purify the residue by silica gel column chromatography (elution system B) to give (1S,3S)-N1-(5-nitropyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 3f, 3.8 g), yield: 97.12%. MS m / z (ESI): 408.1 [M+H] + .

[0256] Step 7: Under a hydrogen atmosphere, Reference Example 3f (3.8 g, 9.33 mmol) and palladium on carbon (993 mg, 0.93 mmol, purity: 10%) were dissolved in methanol (60 mL) and stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine (Reference Example 3 g, 3.2 g). The product did not require purification and was used directly in the next reaction. MS m / z (ESI): 378.1 [M+H] +

[0257] Step 8: Dissolve 3 g (2.0 g, 5.30 mmol) of Reference Example, methyl 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 4.24 mmol) and N,N-diisopropylethylamine (2.05 g, 15.90 mmol) in a mixed solvent of tert-butanol (20 mL) and N,N-dimethylformamide (4 mL), stir at room temperature for 1 hour, then heat to 40 °C and stir for 16 hours, and then heat to 80 °C and stir for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 3, 1.2 g), yield: 45.79%. MS m / z (ESI): 495.2 [M+H] +

[0258] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.75(dd,1H),8.35(d,1H),8.10(d,1H),7.92–7.82(m,2H),7.61(dd,1H),7.15(dd,1H),7 .02(d,1H),6.69(d,1H),6.56(d,1H),4.92(s,2H),4.32-4.13(m,2H),2.23–2.10(m,2H),2.04–1.85(m,2H),1.67–1.43(m,2H).

[0259] See Example 4

[0260] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazol[4,5-b]pyrazin-2-one

[0261]

[0262] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine (Reference Example 4a) (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.78 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 hours. The reaction solution was brought to room temperature, and saturated sodium chloride solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to give 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazol[4,5-b]pyrazin-2-one (Reference Example 4b, 1.4 g, pale yellow solid), yield: 57.87%. MS m / z (ESI): 246.1 [M+H] + .

[0263] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazolium[4,5-b]pyrazin-2-one (Reference Example 4b) (77 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was heated to 130 °C and stirred for 48 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was preparatively separated by reversed-phase HPLC (ammonium bicarbonate system) to give 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-pyrazin-2-one (Reference Example 4) (41 mg, white solid), yield: 30.47%. MS m / z (ESI): 470.1 [M+H] + .

[0264] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(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).

[0265] See Example 5

[0266] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one

[0267]

[0268] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine (Reference Example 4a) (2.2 g, 9.87 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.59 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL). The reaction was heated to 100 °C and stirred for 3 hours. The reaction solution was brought to room temperature, and saturated sodium chloride solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluting system A) to give 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 5b, 1.3 g), yield: 57.49%. MS m / z (ESI): 230.1 [M+H] + .

[0269] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 5b) (72 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was heated to 130 °C and stirred for 48 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was preparatively separated by reversed-phase HPLC (formic acid system) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 5) (46 mg), yield: 35.4%. MS m / z (ESI): 454.1 [M+H] + .

[0270] 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.35(d,1H),8.24(s,2H),8.11(d,1H),7.88(d,1H),7.66-7.57(m,1H),7.48(d,1H),7.25- 6.82(m,1H),6.71(s,1H),6.57(d,1H),4.93(s,2H),4.37-4.19(m,2H),2.22-2.04(m,2H),1.96-1.80(m,2H),1.60-1.41(m,2H).

[0271] See Example 6

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

[0273]

[0274] Step 1: Lithium bis(trimethylsilylamino)ene (1M, 3.6mL) was added to a tetrahydrofuran (3mL) solution of Reference Example 5b (167mg, 0.73mmol) and iodomethane (517mg, 3.64mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. A saturated ammonium chloride solution was added to the reaction mixture at 0°C. The aqueous phase was extracted with ethyl acetate (20mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 6-(6-fluoropyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 6a, 110mg), yield: 58.69%. MS m / z (ESI): 258.1 [M+H] + .

[0275] Step 2: Under nitrogen 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 stirred at 130 °C for 48 hours. Saturated sodium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, concentrated, and the residue was subjected to reversed-phase HPLC to prepare 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 6, 32.1 mg), yield: 24.50%. MS m / z (ESI): 482.3 [M+H] + .

[0276] 1H NMR(400MHz,DMSO-d6)δ8.79-8.69(m,1H),8.29-8.19(m,3H),7.86(d,1H),7.68-7.59(m,1H),7.49(d,1H),7.32-7.26(m,1H ),7.23-6.82(m,1H),6.90(d,1H),6.57(d,1H),4.42-4.20(m,2H),2.23-2.03(m,2H),2.01-1.78(m,2H),1.64-1.34(m,8H).

[0277] Example 1

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

[0279]

[0280] Following the synthetic method of Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one was synthesized. MS m / z (ESI): 438.2 [M+H] + .

[0281] 1 H NMR(400MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.66–7.54(m,2H),7.52–7.36(m,2H),7.09(t,1H),7.01(dd,1H),6.91(d d,2H),6.53(d,1H),6.44(d,1H),6.27(td,1H),4.38–4.11(m,2H),2.21–2.09(m,2H),2.03–1.84(m,2H),1.63–1.44(m,2H).

[0282] Example 3

[0283] 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0284] Example 3 can also be obtained in the following way:

[0285]

[0286] Step 1: Under nitrogen protection, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 3a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bis(triphenylphosphine)palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction mixture was heated to 125 °C and stirred for 5 hours. The reaction mixture was then allowed to return to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added to the reaction mixture. The mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL × 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethane-1-one 3b (445 mg), yield: 67.26%. MS m / z (ESI): 177.1 [M+H] + .

[0287] Step 2: Dissolve 3b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL). Heat the reaction mixture 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 × 2). Combine the organic phases, dry, and concentrate to remove most of the solvent. Add petroleum ether / ethyl acetate = 1 / 1, 10 mL to the residue. Stir at 0 °C for 15 minutes and filter to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethane-1-one 3c (320 mg), yield: 51.05%. MS m / z (ESI): 240.0 [M+H] + .

[0288] 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 stirred for 1 hour. A saturated ammonium chloride solution was slowly added dropwise to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethane-1-ol 3d (136 mg), yield: 96.33%. MS m / z (ESI): 242.0 [M+H] +

[0289] Step 4: Under nitrogen protection, 3d (66 mg, 0.27 mmol), intermediate 2 (57 mg, 0.21 mmol), RuphosPd G4 (18 mg, 0.002 mmol), and sodium tert-butoxide (61 mg, 0.63 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, concentrated, and the residue was subjected to reversed-phase HPLC to prepare 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 3 (1 mg) in 1.10% yield. MS m / z(ESI): 432.2 [M+H] + .

[0290] 1 H NMR(400MHz,DMSO-d6)δ8.49(d,1H),7.92(d,1H),7.61-7.56(m,1H),7.51-7.44(m,1H) ,7.42-7.36(m,1H),7.26(s,1H),6.92(d,1H),6.86-6.81(m,1H),6.57(d,1H),6.53(d,1 H),6.44(d,1H),6.30-6.23(m,1H),5.42(d,1H),4.81-4.69(m,1H),4.39-4.24(m,1H),4 .22-4.09(m,1H),2.20-2.09(m,2H),2.02-1.82(m,2H),1.62-1.43(m,2H),1.34(d,3H).

[0291] Example 4

[0292] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0293]

[0294] Following the synthetic method described in Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 4 was synthesized. MS m / z (ESI): 445.2 [M+H]+ .

[0295] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.65(d,1H),8.36(d,1H),8.14(d,1H),7.87(dd,1H),7.56(dd,1H),7.27(dd,1H),6.86(td,1H),6.74(d ,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.34–4.22(m,1H),4.20– 4.07(m,1H),2.22–2.06(m,2H),2.00–1.81(m,2H),1.63–1.43(m,2H).

[0296] Example 5

[0297] 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0298]

[0299] Following the synthetic method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 5 was synthesized. MS m / z (ESI): 441.2 [M+H] + .

[0300] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.43(d,1H),8.36(d,1H),8.14(dd,1H),7.87(dd,1H),7.56(dd,1H),7.16(s,1H),6.73–6.62(m,2H ),6.54(t,2H),4.97(s,2H),4.38–4.22(m,1H),4.20–4.07(m,1H),2.34(s,3H),2.22–2.06(m,2H),2.02–1.79(m,2H),1.62–1.38(m,2H).

[0301] Example 6

[0302] 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0303]

[0304] Following the synthetic method of Reference Example 1, 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 6 was synthesized. MS m / z (ESI): 454.1 [M+H] + .

[0305] 1 H NMR(400MHz, DMSO-d6)δ8.63(d,1H),7.91(d,1H),7.62–7.56(m,1H),7.47(ddd,1H),7.42(s,1H),7.39(dd,1H),7.13(d,1H),6.92(d,1H),6.78–6. 69(m,2H),6.52(d,1H),6.44(dd,1H),6.27(td,1H),4.37–4.25(m,1H),4. 20–4.07(m,1H),2.19–2.08(m,2H),2.00–1.82(m,2H),1.63–1.41(m,2H).

[0306] Example 7

[0307] 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0308]

[0309] Following the synthetic method of Reference Example 1, 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 7 was synthesized. MS m / z (ESI): 472.2 [M+H] + .

[0310] 1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),7.92(d,1H),7.60(dd,1H),7.51–7.44(m,2H),7.40(dd,1H),6.98–6.87(m,3H),6.52(d,1 H),6.44(dd,1H),6.27(td,1H),4.37–4.26(m,1H),4.22–4.11(m,1H),2.20–2.07(m,2H),2.00–1.82(m,2H),1.61–1.43(m,2H).

[0311] Example 8

[0312] 6'-(((1S,3S)-3-((7-(3-hydroxyazacyclobutane-1-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0313]

[0314] 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 mixture 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 added in portions to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 2,7-dibromo-[1,2,4]triazole[1,5-a]pyridine 8b (2.5 g), yield: 96.2%. MS m / z (ESI): 275.9 [M+H] + .

[0315] Step 2: Under nitrogen protection, 8b (500 mg, 1.81 mmol), 3-hydroxyazacyclobutane 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), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 1-(2-bromo-[1,2,4]triazol[1,5-a]pyridin-7-yl)azacyclobutane-3-hydroxy 8c (100 mg), yield: 20.6%. MS m / z (ESI): 269.0 [M+H] + .

[0316] Step 3: Under nitrogen protection, 8C (100 mg, 0.372 mmol), intermediate 2 (100.5 mg, 0.372 mmol), tris(dibenzylacetone)palladium (34 mg, 0.037 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (35 mg, 0.074 mmol) and cesium carbonate (363 mg, 1.11 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was concentrated and purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product 6'-(((1S,3S)-3-((7-(3-hydroxyazacyclobutane-1-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 8 (10 mg), yield: 5.87%. MS m / z (ESI): 459.2 [M+H] + .

[0317] 1H NMR(400MHz,DMSO-d6)δ8.14(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7.4 1(dd,1H),6.97(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H),6.2 7(td,1H),6.17(d,1H),5.60(d,1H),4.53(m,1H),4.37-4.26(m,1H),4.10(t,2H), 3.90(d,1H),3.67(d,2H),2.22-2.14(m,2H),1.93-1.90(m,2H),1.55-1.51(m,2H).

[0318] Example 9

[0319] 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazacyclobutane-1-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0320]

[0321] Following the synthetic method of Example 8, the target product 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazacyclobutane-1-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 9 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0322] 1 H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H), 7.41(dd,1H),6.98(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H ),6.27(td,1H),6.18(d,1H),5.52(d,1H),4.33(t,1H),3.95-3.86(m,1H),3.8 2-3.74(m,4H),2.24-2.10(m,2H),1.91(t,2H),1.57-1.48(m,2H),1.41(s,3H).

[0323] Example 11

[0324] 6'-(((1S,3S)-3-((7-(2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0325]

[0326] Step 1: Under nitrogen protection, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 11a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bis(triphenylphosphine)palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction mixture was heated to 125 °C and stirred for 5 hours. The reaction mixture was then allowed to return to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added to the reaction mixture. The mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL × 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethane-1-one 11b (445 mg), yield: 67.26%. MS m / z (ESI): 177.1 [M+H] + .

[0327] 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 solution, and continue stirring at 70 °C for 1.5 hours. Add saturated ammonium chloride solution to the reaction solution, extract the aqueous phase with ethyl acetate (20 mL × 2), combine the organic phases, 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, and filter to obtain 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethane-1-one 11c (320 mg), yield: 51.05%. MS m / z (ESI): 240.0 [M+H] + .

[0328] Step 3: Methyl magnesium bromide (1M, 0.7mL) was added dropwise to a 2mL solution of 11c (80mg, 0.33mmol) of tetrahydrofuran at 0℃, and the reaction was stirred at room temperature for 1 hour. A saturated sodium chloride solution was added to the reaction mixture at 0℃, and the aqueous phase was extracted with ethyl acetate (15mL × 2). The organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 11d (60mg) of 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)propane-2-ol, yield: 70.30%. MS m / z (ESI): 256.0 [M+H] + .

[0329] Step 4: Under nitrogen protection, 11d (50 mg, 0.2 mmol), intermediate 2 (63 mg, 0.23 mmol), RuphosPd G4 (17 mg, 0.02 mmol), and sodium tert-butoxide (56 mg, 0.59 mmol) were dissolved in dioxane (1 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. After the reaction mixture was brought to room temperature, saturated sodium chloride solution was added. The aqueous phase was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC to prepare 6'-(((1S,3S)-3-((7-(2-hydroxypropane-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 11 (8.7 mg), yield: 10.00%. MS m / z (ESI): 446.2 [M+H] + .

[0330] 1 H NMR(400MHz,DMSO-d6)δ8.47(d,1H),7.92(d,1H),7.63-7.57(m,1H),7.50 -7.44(m,1H),7.42-7.37(m,1H),7.35(d,1H),6.98-6.86(m,2H),6.60-6.4 9(m,2H),6.44(d,1H),6.31-6.21(m,1H),5.27(s,1H),4.35-4.26(m,1H),4 .20-4.10(m,1H),2.22-2.07(m,2H),2.02-1.80(m,2H),1.62-1.37(m,8H).

[0331] Example 12

[0332] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0333]

[0334] Following the synthetic method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 12 was synthesized. MS m / z (ESI): 495.2 [M+H] + .

[0335] 1 H NMR(400MHz,DMSO-d6)δ8.85–8.74(m,2H),8.36(d,1H),8.14(dd,1H),7.91–7.83(m,2H),7.56(dd,1H),7.15(dd,1H),7.04 (d,1H),6.69(d,1H),6.55(d,1H),4.97(s,2H),4.36–4.15(m,2H),2.23–2.10(m,2H),2.05–1.83(m,2H),1.65–1.42(m,2H).

[0336] Example 13

[0337] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[0338] Example 13 can also be prepared by the following method:

[0339]

[0340] Step 1: Under nitrogen 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) and heated to 130 °C with stirring for 16 hours. The reaction solution was filtered, the filtrate was diluted with saturated sodium chloride solution, extracted with ethyl acetate (30 mL × 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain 2-(6-fluoropyridin-3-yl)pyridazin-3(2H)-one 13b (856 mg), yield: 49.93%. MS m / z (ESI): 192.0 [M+H] + .

[0341] Step 2: Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 13c (710 mg, 3.29 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (856 mg, 4.27 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (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 solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to obtain 13d (473 mg) of ((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester, yield: 42.91%. MS m / z (ESI): 336.2 [M+H] + .

[0342] Step 3: Hydrochloric acid / 1,4-dioxane solution (4M, 3.53mL) was added to a 13d (473mg, 1.41mmol) solution of dichloromethane (4mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in a small amount of dichloromethane and methanol. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution, and the solution was concentrated. The residue was separated by silica gel column chromatography to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 13e (310mg), yield: 93.43%. MS m / z (ESI): 236.1 [M+H] +

[0343] Step 4: Under nitrogen 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). The reaction mixture was heated to 130 °C and stirred for 48 hours. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC to prepare 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one 13 (16.8 mg), yield: 15.80%. MS m / z (ESI): 407.1 [M+H] + .

[0344] 1 H NMR(400MHz,DMSO-d6)δ8.69-8.62(m,1H),8.10(d,1H),8.04-7.98(m,1H),7 .55-7.49(m,1H),7.48-7.43(m,1H),7.30-7.23(m,1H),7.05-6.99(m,1H),6 .94(d,1H),6.89-6.82(m,1H),6.75(d,1H),6.53(d,1H),4.39-4.26(m,1H), 4.22-4.07(m,1H),2.21-2.09(m,2H),2.01-1.83(m,2H),1.63-1.42(m,2H).

[0345] Example 14

[0346] 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0347]

[0348] Following the synthetic method of Reference Example 1, 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one 14 was synthesized. MS m / z (ESI): 402.2 [M+H] + .

[0349] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd,1H),7.39(dd,1H),7.28(d,2H),6.92(d,1H),6.53(d,2H),6 .44(d,1H),6.26(td,1H),4.36–4.26(m,1H),4.22–4.08(m,1H),2.27(s,3H),2.20–2.09(m,2H),1.99–1.82(m,2H),1.59–1.44(m,2H).

[0350] Example 15

[0351] 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0352]

[0353] Following the synthetic method of Reference Example 1, 15 oz. of 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one was synthesized. MS m / z (ESI): 424.2 [M+H] + .

[0354] 1 H NMR(400MHz,DMSO-d6)δ9.22(dd,1H),8.15(s,1H),7.91(d,1H),7.63–7.54(m,2H),7.47(ddd,1H),7.39(dd,1H),6.92(d,1H),6.80(d,1H),6 .52(d,1H),6.47–6.41(m,1H),6.27(td,1H),4.38–4.26(m,1H),4.20– 4.08(m,1H),2.20–2.08(m,2H),2.03–1.83(m,2H),1.63–1.42(m,2H).

[0355] Example 18

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

[0357]

[0358] Following the synthetic method of Reference Example 1, 6'-(((1S,3S)-3-((7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 18 was synthesized. MS m / z (ESI): 418.2 [M+H] + .

[0359] 1 H NMR(400MHz,DMSO-d6)δ8.40(d,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd,1H),7.39(dd,1H),6.91(d,1H),6.81(d,1H),6.55–6.41 (m,4H),6.26(td,1H),4.37–4.25(m,1H),4.19–4.05(m,1H),3.82(s,3H),2.20–2.07(m,2H),2.01–1.82(m,2H),1.61–1.43(m,2H).

[0360] Example 19

[0361] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0362] Example 19 can also be prepared by the following method:

[0363]

[0364] Step 1: Under nitrogen 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 mixture was heated to 130 °C and stirred for 48 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to reversed-phase HPLC to prepare 19 (7.3 mg) of 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, yield: 9.94%. MS m / z (ESI): 473.3 [M+H] + .

[0365] 1 H NMR(400MHz,DMSO-d6)δ8.80-8.72(m,1H),8.70-8.62(m,1H),8.27-8.19(m,1H),7.85(d,1H),7.69-7.60(m,1H),7.34-7.23(m,2H),6.9 3-6.81(m,2H),6.75(d,1H),6.57(d,1H),4.37-4.26(m,1H),4.22-4.10(m,1H),2.22-2.08(m,2H),2.02-1.84(m,2H),1.64-1.34(m,8H).

[0366] Example 20

[0367] 3-Fluoro-6-(6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0368]

[0369] Following the synthetic method of Reference Example 2, 3-fluoro-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 20 was synthesized. MS m / z (ESI): 463.2 [M+H] + .

[0370] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.66(dd,1H),8.33(d,1H),8.09(dd,1H),7.85(dd,1H),7.27(dd,1H),6.88-6.84(m,1H),6.74(d,1H),6.71(d ,1H),6.55(d,1H),4.93(s,2H),4.32-4.27(m,1H),4.18-4.13(m,1H),2. 19-2.09(m,2H),2.01-1.93(m,1H),1.90-1.83(m,1H),1.59-1.46(m,2H).

[0371] Example 21

[0372] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0373]

[0374] Following the synthetic method described in Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 21 was synthesized. MS m / z (ESI): 446.2 [M+H] + .

[0375] 1 H NMR (400MHz, DMSO-d6) δ8.86–8.79(m,2H),8.66(dd,1H),8.40(d,1H),7.91(dd,1H),7.27(dd,1H),6.88–6.81(m,1H),6.74(dd ,2H),6.56(d,1H),5.02(s,2H),4.37–4.23(m,1H),4.21–4.08(m,1H),2.21–2.06(m,2H),1.99–1.83(m,2H),1.62–1.44(m,2H).

[0376] Example 22

[0377] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0378]

[0379] Following the synthetic method of Reference Example 3, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 22 was synthesized. MS m / z (ESI): 496.2 [M+H] + .

[0380] 1H NMR (400MHz, DMSO-d6) δ9.41(s,1H),9.23(s,1H),8.82(d,1H),8.37(d,1H),7.89-7.85(m,2H),7.15(dd,1H),7.04(d,1H),6.80( d,1H),6.57(d,1H),5.02(s,2H),4.34-4.29(m,1H),4.24-4.18(m,1H),2.20-2.13(m,2H),2.01-1.89(m,2H),1.62-1.46(m,2H).

[0381] Example 23

[0382] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(2-hydroxypropane-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0383]

[0384] Following the synthetic method of Reference Example 2, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(2-hydroxypropane-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 23 was synthesized. MS m / z (ESI): 503.2 [M+H] + .

[0385] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),8.34(d,1H),8.06(d,1H),7.90( d,1H),7.87-7.81(m,1H),7.30-7.23(m,1H),6.90-6.82(m,1H),6.75(d,1H ),6.69(d,1H),6.56(d,1H),5.40(s,1H),4.88(s,2H),4.37-4.23(m,1H),4 .21-4.07(m,1H),2.21-2.05(m,2H),2.01-1.81(m,2H),1.62-1.39(m,8H).

[0386] Example 25

[0387] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one

[0388]

[0389] Following the synthetic method of Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one 25 μL was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0390] 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.30(d,1H),7.95(d,1H),7.90–7.77(m,3H),7.27(dd,1H),6.86(t,1H),6.75(d,1 H),6.68(d,1H),6.54(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.15(dd,2H),2.01–1.84(m,2H),1.61–1.44(m,2H).

[0391] Example 26

[0392] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one

[0393]

[0394] Following the synthetic method of Reference Example 2, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one 26 was synthesized. MS m / z (ESI): 512.1 [M+H] + .

[0395] 1H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.36(d,1H),8.03(dd,2H),7.89–7.70(m,2H),7.27(dd,1H),6.86(t,1H) ,6.72(dd,2H),6.54(d,1H),5.10(d,2H),4.22(d,2H),2.21–2.06(m,2H),2.00–1.81(m,2H),1.64–1.42(m,2H).

[0396] Example 27

[0397] 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0398]

[0399] Following the synthetic method of Reference Example 3, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 27 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0400] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.75(s,1H),8.33(d,1H),8.09(dd,1H),7.87-7.83(m,2H),7.15(dd,1H),7.04(d,1H),6.72 (d,1H),6.56(d,1H),4.93(s,2H),4.35–4.29(m,1H),4.25–4.17(m,1H),2.20-2.13(m,2H),2.00-1.86(m,2H),1.62–1.48(m,2H).

[0401] Example 28

[0402] 3-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one

[0403]

[0404] Alternatively, referring to the synthetic method in Reference Example 1, the target product 3-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one 28 was synthesized. MS m / z (ESI): 407.2 [M+H] + .

[0405] 1 H NMR(400MHz,DMSO-d6)δ8.73-8.58(m,1H),8.39(s,1H),8.01-7.90(m,2H),7.48-7.40(m,1H),7.30-7.23(m,1H),7.03(d,1H),6.90-6.82(m ,1H),6.75(d,1H),6.55(d,1H),6.47(d,1H),4.39-4.26(m,1H),4.24- 4.09(m,1H),2.21-2.08(m,2H),2.02-1.80(m,2H),1.65-1.40(m,2H).

[0406] Example 29

[0407] 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazin-2(1H)-one

[0408]

[0409] Alternatively, referring to the synthetic method of Reference Example 1, the target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazin-2(1H)-one 29 was synthesized. MS m / z (ESI): 407.1 [M+H] + .

[0410] 1H NMR(400MHz,DMSO-d6)δ8.70-8.61(m,1H),8.07(s,1H),8.02(d,1H),7.63(d,1H),7.52-7.45(m,1H),7.36(d,1H),7.31-7.23(m,1H),7.04(d,1 H),6.90-6.81(m,1H),6.75(d,1H),6.55(d,1H),4.39-4.26(m,1H),4.2 2-4.10(m,1H),2.21-2.06(m,2H),2.02-1.80(m,2H),1.64-1.42(m,2H).

[0411] Example 31

[0412] 6'-(3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridine]-2(1H)-one

[0413] Example 31 can also be prepared by the following method:

[0414]

[0415] Step 1: Under nitrogen protection, (1S,3S)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (200 mg, 0.9 mmol), 5-bromo-2-fluoropyridine (195 mg, 1.1 mmol), and N,N-diisopropylethylamine (330 mg, 2.6 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the reaction 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) to obtain N 1 -(5-bromopyridin-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 31a (200 mg), yield: 60%. MS m / z (ESI): 391.0 [M+H] + .

[0416] Step 2: Under nitrogen protection, 31a (170 mg, 0.4 mmol), (2-oxo-1H-pyridin-3-yl)boronic acid (60 mg, 0.4 mmol), and sodium carbonate (92 mg, 0.9 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). 1,1-bis(diphenylphosphine)diberberine palladium dichloride (64 mg, 0.1 mmol) was added, and the reaction was heated to 80 °C and stirred for 1 hour. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 6'-(3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]-[3,3'-bipyridine]-2(1H)-one 31 (90 mg), yield: 51%. MS m / z (ESI): 406.1 [M+H] + .

[0417] 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.66(dd,1H),8.34(d,1H),7.77(dd,1H),7.54(dd,1H),7.31–7.24(m,2H),6.86 (td,1H),6.71(dd,2H),6.46(d,1H),6.23(t,1H),4.31(q,1H),4.15(d,1H),2.13(dt,2H),1.91(dd,2H),1.52(dd,2H).

[0418] Example 32

[0419] 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropane-2-yl)-2H-[1,3'-bipyridine]-2-one

[0420]

[0421] Step 1: Under nitrogen 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). The reaction mixture was heated to 130 °C and stirred for 16 hours. A saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, 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]pyridin-2-yl)-N 3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine 32a (95 mg), yield: 51.00%. MS m / z (ESI): 439.0 [M+H] + .

[0422] Step 2: Under nitrogen protection, 32a (50 mg, 0.11 mmol), 3-(2-hydroxypropane-2-yl)pyridin-2(1H)-one (35 mg, 0.23 mmol), cuprous iodide (22 mg, 0.11 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (16 mg, 0.11 mmol) and cesium carbonate (112 mg, 0.34 mmol) were dissolved in 1,4-dioxane (1 mL), and the reaction was heated to 105 °C and stirred for 2 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC to prepare 32 (25.1 mg) of 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-3-(2-hydroxypropane-2-yl)-2H-[1,3'-bipyridine]-2-one, yield: 47.46%. MS m / z (ESI): 464.2 [M+H] + .

[0423] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),7.91(d,1H),7.65-7.59(m,1H),7.5 6-7.52(m,1H),7.42-7.37(m,1H),7.30-7.24(m,1H),6.91(d,1H),6.89-6.83(m ,1H),6.75(d,1H),6.53(d,1H),6.34-6.28(m,1H),5.33(s,1H),4.38-4.24(m,1 H),4.22-4.09(m,1H),2.22-2.07(m,2H),2.04-1.81(m,2H),1.64-1.37(m,8H).

[0424] Example 33

[0425] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-methyl-5,6-dihydro-7H-pyrrole[3,4-d]pyrimidin-7-one

[0426]

[0427] Following the synthetic method of Reference Example 2, the target product 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-methyl-5,6-dihydro-7H-pyrrole[3,4-d]pyrimidin-7-one 33 was synthesized. MS m / z (ESI): 460.2 [M+H] + .

[0428] 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.65(dd,1H),8.36(d,1H),7.87(dd,1H),7.27(dd,1H),6.86(td,1H),6.75(dd,2H), 6.56(d,1H),4.96(s,2H),4.30(q,1H),4.15(q,1H),2.76(s,3H),2.19-2.09(m,2H),2.00-1.83(m,2H),1.59-1.46(m,2H).

[0429] Example 49

[0430] 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0431]

[0432] Step 1: Diisopropylaminolithium (2M, 1.05mL) was added dropwise to a tetrahydrofuran (5mL) solution of 2-bromo-6-tert-butylpyridine 49a (300mg, 1.40mmol) at -78℃. The reaction was stirred at -78℃ for 1 hour. Then, N,N-dimethylformamide (410mg, 5.60mmol) was added dropwise to the reaction solution. The reaction was slowly raised to room temperature and stirred for 1 hour. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (25mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain 2-bromo-6-(tert-butyl)nicotinaldehyde 49b (56mg), yield: 16.51%. MS m / z (ESI): 242.0 [M+H] + .

[0433] Step 2: Under carbon monoxide protection, 49b (53 mg, 0.22 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (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 mixture was heated to 80 °C and stirred for 16 hours. A saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain methyl 6-(tert-butyl)-3-carboxypyridinecarboxylate 49c (13 mg), yield: 26.84%. MS m / z (ESI): 222.1 [M+H] + .

[0434] Step 3: Dissolve Reference Example 2e (23 mg, 0.07 mmol), 49c (13 mg, 0.06 mmol), and acetic acid (5 mg, 0.09 mmol) in 1,2-dichloroethane (2 mL). Heat the reaction mixture to 60 °C and stir for 1 hour. After the reaction mixture has returned to room temperature, add sodium triacetoxyborohydride (62 mg, 0.29 mmol) and stir for 15 hours. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC to prepare 49 (15.8 mg) of 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, yield: 53.72%. MS m / z (ESI): 501.2 [M+H] + .

[0435] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),8.34(d,1H),8.02(d,1H),7.89- 7.80(m,1H),7.68(d,1H),7.31-7.22(m,1H),6.90-6.82(m,1H),6.75(d,1H ),6.68(d,1H),6.56(d,1H),4.86(s,2H),4.35-4.23(m,1H),4.22-4.08(m, 1H),2.22-2.07(m,2H),2.03-1.81(m,2H),1.63-1.42(m,2H),1.37(s,9H).

[0436] Example 50

[0437] 2-(6-((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one

[0438]

[0439] Following the synthetic method of Reference Example 2, 50 mmol of 2-(6-((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one was synthesized. MS m / z (ESI): 461.1 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.66(dd,1H),8.32(d,1H),7.80(dd,1H),7.55(d,1H),7.27(dd,1H),6.86(td,J=7.6,2.8Hz,1H ),6.74(d,J=7.3Hz,1H),6.67(d,1H),6.50(dd,2H),4.73(s,2H),4.28(q,1H),4.15(q,1H),2.14(dq,2H),1.90(dq,2H),1.51(dd,2H).

[0441] Example 51

[0442] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0443]

[0444] Step 1: At room temperature, methyl 5-amino-2-bromo-pyridine-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 solution was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give methyl 3-amino-2,6-dibromo-pyridine-4-carboxylate 51a (12.5 g), yield: 93.18%. MS m / z (ESI): 308.9, 310.9, 312.9 [M+H]+ .

[0445] Step 2: Under nitrogen protection, 51a (12.4 g, 40.01 mmol), a tetrahydrofuran solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxazoborane (3.5 M, 23 mL), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.91 g, 4.00 mmol), tris(dibenzylacetone)dipalladium (1.83 g, 2.0 mmol), and potassium phosphate (17.0 g, 80.01 mmol) were dissolved in 1,4-dioxane (100 mL). The mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give methyl 3-amino-2,6-dimethylisonicotinic acid ester 51b (5 g), yield: 69.35%. MS m / z(ESI): 181.1 [M+H] + .

[0446] 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 solution. The reaction was stirred at room temperature for 30 minutes, then heated to 60 °C and stirred for 1 hour. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give methyl 3-bromo-2,6-dimethylisonicotinic acid ester 51c (4.9 g), yield: 75.37%. MS m / z (ESI): 244.0, 246.0 [M+H] + .

[0447] Step 4: Under nitrogen protection, 51c (500 mg, 2.05 mmol), potassium tert-butoxymethyltrifluoroborate (795.0 mg, 4.10 mmol), tris(dibenzylacetone)dipalladium (187.6 mg, 0.20 mmol), 2-dicyclohexylphosphine-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 mixture was heated to 120 °C and stirred for 16 hours. The reaction solution was diluted with dichloromethane (40 mL), the organic phase was washed with water, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain methyl 3-(tert-butoxymethyl)-2,6-dimethylisonicotinic acid ester 51d (300 mg), yield: 58.27%. MS m / z(ESI): 252.0 [M+H] + .

[0448] Step 5: At room temperature, 51d (300 mg, 1.19 mmol) was dissolved in dichloromethane (7 mL). Trifluoroacetic acid (409.02 mg, 3.59 mmol) was added dropwise to the reaction solution and stirred for 1 hour. The reaction solution was concentrated, and 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 give 4,6-dimethylfurano[3,4-c]pyridin-1(3H)-one 51e (120 mg), yield: 61.61%. MS m / z (ESI): 164.1 [M+H] + .

[0449] Step 6: Under nitrogen 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 solution, and the mixture was heated to 90 °C and stirred for 1 hour. The reaction solution was then added dropwise to methanol (10 mL) while stirring, and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(hydroxymethyl)-2,6-dimethylisonicotinamide 51f (30 mg), yield: 28.6%. MS m / z (ESI): 491.2 [M+H] + .

[0450] 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 azodicarbonate (16.5 mg, 0.08 mmol) was added. The mixture was stirred for 16 hours. The reaction solution 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]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 51 (1.2 mg), yield: 6.23%. MS m / z (ESI): 473.2 [M+H] + .

[0451] 1H NMR(400MHz,DMSO-d6)δ8.69–8.62(m,1H),8.36(d,1H),7.86(dd,1H),7.40(s,1H),7.27(dd,1H),6.86(td,1H),6.72(dd,2H),6.5 4(d,1H),4.93(s,2H),4.32–4.23(m,1H),4.18–4.10(m,1H),2.55(s,6H),2.19–2.07(m,2H),1.99–1.82(m,2H),1.60–1.45(m,2H).

[0452] Example 52

[0453] 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)piperidin-2-one

[0454]

[0455] Following the synthetic method of Example 32, the target product 1-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)piperidin-2-one 52 was synthesized. MS m / z (ESI): 410.2 [M+H] + .

[0456] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.60(m,1H),7.81(d,1H),7.31-7.20(m,2H),6.90-6.81(m,1H),6.73(d,1H),6.60(d,1H),6.44(d,1H), 4.31-4.20(m,1H),4.19-4.08(m,1H),3.56-3.43(m,2H),2.40-2.27(m,2H),2.20-2.04(m,2H),2.01-1.72(m,6H),1.64-1.37(m,2H).

[0457] Example 53

[0458] 4-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)morpholin-3-one

[0459]

[0460] Following the synthesis method of Example 32, the target product 4-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)morpholin-3-one 53 was synthesized. MS m / z (ESI): 412.2 [M+H] + .

[0461] 1 H NMR (400MHz, DMSO-d6) δ8.71-8.61(m,1H),7.92(d,1H),7.37-7.31(m,1H),7.30-7.23(m,1H),6.90-6.82(m,1H),6.77-6.67(m,2H),6.47(d ,1H),4.32-4.21(m,1H),4.20-4.08(m,3H),3.98-3.88(m,2H),3.67- 3.57(m,2H),2.19-2.06(m,2H),1.99-1.79(m,2H),1.63-1.39(m,2H).

[0462] Example 54

[0463] 5-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2,4]heptane-4-one

[0464]

[0465] Following the synthetic method of Example 32, the target product 5-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2,4]heptane-4-one 54 was synthesized. MS m / z (ESI): 422.2 [M+H] + .

[0466] 1H NMR(400MHz,DMSO-d6)δ8.69-8.61(m,1H),8.11(d,1H),7.74-7.64(m,1H), 7.31-7.21(m,1H),6.90-6.81(m,1H),6.73(d,1H),6.53(d,1H),6.47(d,1H ),4.30-4.20(m,1H),4.19-4.08(m,1H),3.81(t,2H),2.22-2.05(m,4H),1. 99-1.77(m,2H),1.62-1.37(m,2H),0.95--0.89(m,2H),0.85-0.79(m,2H).

[0467] Example 55

[0468] 6-(6-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0469]

[0470] Following the synthetic method described in Reference Example 3, 6-(6-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 55 was synthesized. MS m / z (ESI): 467.2 [M+H] + .

[0471] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.44–8.31(m,2H),8.10(d,1H),7.87(dd,1H),7.61(dd,1H),7.06(s,1H),6.72–6.43(m,4H) ,4.92(s,2H),4.32–4.23(m,1H),4.18–4.10(m,1H),2.23–2.07(m,2H),2.05–1.81(m,4H),1.62–1.40(m,3H),1.37–1.26(m,2H).

[0472] Example 56

[0473] 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0474]

[0475] Following the synthetic method described in Reference Example 3, 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 56 was synthesized. MS m / z (ESI): 493.2 [M+H] + .

[0476] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.63(d,1H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.65–7.58(m,1H),7.42(t,1H),7.14(d,1H),6 .78–6.66(m,3H),6.55(d,1H),4.92(s,2H),4.32–4.23(m,1H),4.20– 4.07(m,1H),2.20–2.08(m,2H),2.01–1.82(m,2H),1.60–1.43(m,2H).

[0477] Example 56 can also be synthesized using the following method:

[0478]

[0479] Step 1: Under nitrogen 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(dibenzylacetone)palladium (173.4 mg, 0.19 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (219.2 mg, 0.38 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was microwaved to 130 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to give tert-butyl N-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]carbamate 56a (170 mg), yield: 46.8%. MS m / z (ESI): 384.2 [M+H] + .

[0480] Step 2: At room temperature, 56a (170 mg, 0.44 mmol) was dissolved in methanol (7 mL), and hydrochloric acid (4 M, 4 mL) was added. The mixture was stirred for half an hour. The reaction solution was concentrated, and the residue was diluted with methanol. The pH of the mixture 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)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine 56b (120 mg), yield: 95.5%. MS m / z (ESI): 284.2 [M+H] + .

[0481] Step 3: At room temperature, 56b (140 mg, 0.49 mmol), 2-fluoro-5-nitro-pyridine (77.2 mg, 0.54 mmol), and cesium carbonate (322.0 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the mixture was heated to 80 °C and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give (1S,3S)-N3-[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-N1-(5-nitro-2-pyridyl)cyclopentane-1,3-diamine 56c (50 mg), yield: 25.0%. MS m / z (ESI): 406.2 [M+H] + .

[0482] Step 4: Under a hydrogen atmosphere, 56c (50 mg, 0.12 mmol) and palladium on carbon (13.1 mg, 0.012 mmol, purity: 10%) were dissolved in methanol (10 mL) and stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to give N2-[(1S,3S)-3-[[7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridine-2,5-diamine 56d (35 mg), yield: 75.6%. MS m / z (ESI): 376.1 [M+H] + .

[0483] 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), and the mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative thin-layer chromatography (elution system A) to give 6-(6-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 56 (11 mg), yield: 24.0%. MS m / z(ESI): 493.2 [M+H] + .

[0484] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.63(d,1H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.65–7.58(m,1H),7.42(t,1H),7.14(d,1H),6 .78–6.66(m,3H),6.55(d,1H),4.92(s,2H),4.32–4.23(m,1H),4.20– 4.07(m,1H),2.20–2.08(m,2H),2.01–1.82(m,2H),1.60–1.43(m,2H).

[0485] Example 57

[0486] 4-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0487]

[0488] Step 1: At room temperature, 3 g (100 mg, 0.26 mmol) of Reference Example, methyl 3-(bromomethyl)-2-chloroisonicotinic acid (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 stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 4-chloro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 57a (90 mg), yield: 64.21%. MS m / z (ESI): 529.1 [M+H] + .

[0489] Step 2: Under nitrogen protection, 57a (90 mg, 0.17 mmol), a tetrahydrofuran solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxazoborane (3.5 M, 0.15 mL), 2-dicyclohexylphosphine-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), and the mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography (elution system A) to give 57 (56.6 mg) of 4-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, yield: 65.41%. MS m / z (ESI): 509.1 [M+H] + .

[0490] 1H NMR (400MHz, DMSO-d6) δ8.82(d,1H),8.63(d,1H),8.38(d,1H),7.91–7.82(m,2H),7.54(d,1H),7.15(dd,1H),7.03(d,1H),6. 73(s,1H),6.57(d,1H),4.98(s,2H),4.37–4.14(m,2H),2.57(s,3H),2.21–2.10(m,2H),2.03–1.86(m,2H),1.64–1.44(m,2H).

[0491] Example 58

[0492] 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-

[0493] 5-azaspiro[2,4]heptane-4-one

[0494]

[0495] Step 1: Add 3 g (70 mg, 0.19 mmol) of reference example to a solution of p-toluenesulfonic acid (96 mg, 0.56 mmol) in acetonitrile (1.5 mL). Cool the reaction solution to 0 °C. Add a solution of sodium nitrite (26 mg, 0.37 mmol) and potassium iodide (80 mg, 0.48 mmol) in water (0.5 mL). Stir the reaction solution at room temperature for 48 hours. Add a saturated sodium chloride solution to the reaction solution. Extract the aqueous phase with ethyl acetate (20 mL × 2). Combine the organic phases, dry, concentrate, and separate the residue by silica gel column chromatography to obtain (1S,3S)-N1-(5-iodopyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 58a (37 mg), yield: 40.85%. MS m / z (ESI): 489.1 [M+H] + .

[0496] Step 2: Following the synthesis method described in Example 32, 5-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-azaspiro[2,4]heptane-4-one 58 was synthesized. MS m / z (ESI): 472.2 [M+H] + .

[0497] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.11(d,1H),7.85(s,1H),7.74-7.64(m,1H),7.19-7.10(m,1H),7.02(d,1H),6.54(d,1H),6.47(d,1 H),4.32-4.11(m,2H),3.87-3.74(m,2H),2.23-2.07(m,4H),2.00-1.80(m,2H),1.65-1.38(m,2H),0.95-0.90(m,2H),0.85-0.79(m,2H).

[0498] Example 59

[0499] 4,6-Dimethyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0500]

[0501] Following the synthetic method of Reference Example 3, 4,6-dimethyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 59g was synthesized. MS m / z (ESI): 523.2 [M+H] + .

[0502] Example 60

[0503] 3-Methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)

[0504] pyridin-3-yl)methylpyridine amide

[0505]

[0506] Step 1: Dissolve 3g (50mg, 0.13mmol) of reference example, 20mg (0.15mmol) of 3-methyl-2-pyridinecarboxylic acid, and 33mg (0.4mmol) of N-methylimidazolium (1.5mL) in acetonitrile. Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56mg, 0.2mmol) to the above reaction solution and stir at room temperature for 2 hours. Saturated sodium chloride solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC to prepare 60 (9.7 mg) of 3-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpyridineamide, yield: 14.75%. MS m / z (ESI): 497.2 [M+H] + .

[0507] 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.82(d,1H),8.51(d,1H),8.33(d,1H),7.85(s,1H),7.82-7.75(m,2H),7.53-7.44(m,1H),7.18- 7.11(m,1H),7.03(d,1H),6.52-6.43(m,2H),4.33-4.13(m,2H),2.56(s,3H),2.21-2.08(m,2H),2.01-1.82(m,2H),1.64-1.41(m,2H).

[0508] Example 61

[0509] 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0510]

[0511] Following the synthetic method described in Reference Example 3, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 61 was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0512] 1 H NMR(400MHz,DMSO-d6)δ8.87–8.76(m,2H),8.36(d,1H),8.10(dd,1H),7.86(dd,2H),7.15(dd,1H),7.02(d,1H),6 .71(d,1H),6.55(d,1H),4.96(d,2H),4.38–4.12(m,2H),2.24–2.10(m,2H),2.05–1.83(m,2H),1.63–1.42(m,2H).

[0513] Example 62

[0514] N-Methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpyridineamide

[0515]

[0516] Step 1: 2-Fluoro-5-aminopyridine 62a (500 mg, 4.46 mmol), pyridine-2-carboxylic acid (604 mg, 4.91 mmol), and N-methylimidazolium (1.10 g, 13.38 mmol) were dissolved in acetonitrile (15 mL). N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.88 g, 6.69 mmol) was added to the above reaction solution, and the mixture was stirred at room temperature for 3 hours. Saturated sodium chloride solution (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, and concentrated. 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, the mixture was filtered to obtain N-(6-fluoropyridin-3-yl)methylpyridine amide 62b (464 mg), yield: 47.90%. MS m / z(ESI): 218.1 [M+H] + .

[0517] Step 2: Sodium hydride (128 mg, 3.20 mmol, 60% purity) was added to a 10 mL solution of 62b (464 mg, 2.14 mmol) in tetrahydrofuran at 0 °C. After 30 minutes, methyl iodide (606 mg, 4.27 mmol) was added to the reaction solution. The reaction mixture was slowly heated to room temperature and stirred for 1.5 hours. A saturated sodium chloride solution (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography to obtain N-(6-fluoropyridin-3-yl)-N-methylmethylpyridinamide 62c (53 mg), yield: 10.73%. MS m / z (ESI): 232.1 [M+H] + .

[0518] Step 3: Reference Example 3e (68 mg, 0.18 mmol), 62c (54 mg, 0.23 mmol), and N,N-diisopropylethylamine (69 mg, 0.54 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was heated to 130 °C and stirred for 60 hours. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC to prepare N-methyl-N-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)methylpyridineamide 62 (4.2 mg), yield: 4.73%. MS m / z (ESI): 497.2 [M+H] + .

[0519] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.33(d,1H),7.84(s,1H),7.76-7.68(m,1H),7.63(s,1H),7.40(d,1H),7.27-7.19(m,2H),7.17-7.1 1(m,1H),6.96(d,1H),6.60(d,1H),6.29(d,1H),4.22-4.05(m,2H),3 .29(s,3H),2.13-2.01(m,2H),1.93-1.70(m,2H),1.60-1.31(m,2H).

[0520] Example 63

[0521] 3-(2-hydroxypropane-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0522]

[0523] Following the synthetic method of Example 58, 3-(2-hydroxypropan-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 63 was synthesized. MS m / z (ESI): 514.2 [M+H] + .

[0524] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),7.91(d,1H),7.85(s,1H),7.50(d,1H), 7.42-7.35(m,1H),7.18-7.12(m,1H),7.02(d,1H),6.89(d,1H),6.52(d,1H), 6.46(d,1H),6.38-6.33(m,1H),5.15(s,1H),4.40-4.28(m,1H),4.27-4.15( m,1H),2.23-2.09(m,2H),2.03-1.84(m,2H),1.65-1.44(m,2H),1.38(s,6H).

[0525] Example 65

[0526] 5-Carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-carboxynitrile

[0527]

[0528] Following the synthetic method of Reference Example 3, 5-carbonyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-carboxynitrile 65 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0529] 1H NMR(400MHz,DMSO-d6)δ9.24(d,1H),8.82(d,1H),8.71(d,1H),8.37(d,1H),7.87(dd,1H),7.85(s,1H),7.15(dd,1H),7.03(d,1H),6 .74(d,1H),6.56(d,1H),5.09(s,2H),4.34-4.29(m,1H),4.23-4.18(m,1H),2.18-2.12(m,2H),2.01-1.88(m,2H),1.59-1.49(m,2H).

[0530] Example 66

[0531] 1-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-carboxynitrile

[0532]

[0533] Following the synthetic method of Reference Example 3, 1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-carboxynitrile 66 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0534] 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.82(d,1H),8.41(s,1H),8.35(d,1H),7.86-7.82(m,2H),7.15(dd,1H),7.01(d,1H),6.77( d,1H),6.57(d,1H),5.12(s,2H),4.34-4.29(m,1H),4.24-4.19(m,1H),2.20-2.13(m,2H),2.00-1.88(m,2H),1.61-1.50(m,2H).

[0535] Example 67

[0536] 2-Methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0537]

[0538] Following the synthetic method of Reference Example 3, 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 67 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0539] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.35(d,1H),8.01(d,1H),7.91-7.78(m,2H),7.42(d,1H),7.14(d,1H),7.01(d,1H),6.64(d,1H), 6.55(d,1H),4.90(s,2H),4.33-4.27(m,1H),4.23-4.18(m,1H),2.62(s,3H),2.18-2.13(m,2H),2.00-1.89(m,2H),1.60-1.49(m,2H).

[0540] Example 68

[0541] 2-Cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0542]

[0543] Following the synthetic method of Reference Example 3, 2-cyclopropyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 68 was synthesized. MS m / z (ESI): 535.2 [M+H] + .

[0544] 1 H NMR (400MHz, DMSO-d6) δ8.82(d,1H),8.32(d,1H),7.96(d,1H),7.88-7.83(m,2H),7.46(d,1H),7.14(dd,1H),7.02(d,1H),6.63(d,1H),6. 53(d,1H),4.85(s,2H),4.32-4.18(m,2H),2.31-2.25(m,1H),2.18-2 .12(m,2H),2.01-1.85(m,2H),1.61-1.47(m,2H),1.10-1.01(m,4H).

[0545] Example 69

[0546] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octane-5-yl)pyridin-2-yl)-N3-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0547]

[0548] Following the synthetic method of Example 58, (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octane-5-yl)pyridin-2-yl)-N3-(7-fluoro-[1,2.4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 69 was synthesized. MS m / z (ESI): 424.2 [M+H] + .

[0549] Example 70

[0550] (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octane-5-yl)pyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0551]

[0552] Following the synthetic method of Example 58, (1S,3S)-N1-(5-(2-oxa-5-azaspiro[3.4]octane-5-yl)pyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2.4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 70 was synthesized. MS m / z (ESI): 474.2 [M+H] + .

[0553] Example 71

[0554] 6-Cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0555]

[0556] Following the synthetic method of Reference Example 3, 6-cyclopropyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 71 was synthesized. MS m / z (ESI): 535.2 [M+H] + .

[0557] Example 72

[0558] 3-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-carboxynitrile

[0559]

[0560] Following the synthetic method of Reference Example 3, 3-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-carboxynitrile 72 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0561] Example 73

[0562] 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridine]-2(1H)-one

[0563]

[0564] Following the synthetic method of Example 31, 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-[3,3'-bipyridine]-2(1H)-one 73 was synthesized. MS m / z (ESI): 456.2 [M+H] + .

[0565] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.81(d,1H),8.35(d,1H),7.84(s,1H),7.77(dd,1H),7.54(dd,1H),7.28(d,1H),7.14(dd,1H),7.00(d ,1H),6.66(d,1H),6.46(d,1H),6.23(t,1H),4.35–4.30(m,1H),4.23– 4.18(m,1H),2.19–2.12(m,2H),2.01-1.88(m,2H),1.61–1.49(d,2H).

[0566] Example 75

[0567] 3-Fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0568]

[0569] Following the synthetic method of Reference Example 3, 75 ppm of 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one was synthesized. MS m / z (ESI): 513.2 [M+H] + .

[0570] 1H NMR(400MHz,DMSO-d6)δ8.87–8.76(m,2H),8.36(d,1H),8.10(dd,1H),7.86(dd,2H),7.15(dd,1H),7.02(d,1H),6 .71(d,1H),6.55(d,1H),4.96(d,2H),4.40–4.15(m,2H),2.24–2.10(m,2H),2.05–1.83(m,2H),1.65–1.41(m,2H).

[0571] Example 76

[0572] 1-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-carboxynitrile

[0573]

[0574] Following the synthetic method of Reference Example 3, 1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-carboxynitrile 76 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0575] 1 H NMR(400MHz,DMSO-d6)δ8.94(d,1H),8.82(d,1H),8.41(d,1H),8.08(d,1H),7.91-7.81(m,2H),7.18-7.11(m,1H),7.02(d,1H),6.7 8(d,1H),6.57(d,1H),5.25(s,2H),4.38-4.28(m,1H),4.26-4.16(m,1H),2.24-2.10(m,2H),2.05-1.83(m,2H),1.67-1.43(m,2H).

[0576] Example 77

[0577] 3-Carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-carboxynitrile

[0578]

[0579] Following the synthetic method of Reference Example 3, 3-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-7-carboxynitrile 77 was synthesized. MS m / z (ESI): 520.2 [M+H] + .

[0580] Example 78

[0581] 4-Hydroxy-1-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-2(1H)-one

[0582]

[0583] Following the synthetic method of Example 58, 4-hydroxy-1-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-2(1H)-one 78 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0584] 1 H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.82(d,1H),7.94(d,1H),7.85(s,1H),7.62(d,1H),7.42-7.35(m,1H),7.20-7.10(m,1H),7.03(d,1H) ,6.93(d,1H),6.51(d,1H),5.65-5.56(m,1H),4.38-4.26(m,1H),4.25 -4.14(m,1H),2.21-2.09(m,2H),2.02-1.82(m,2H),1.66-1.40(m,2H).

[0585] Example 79

[0586] 5-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0587]

[0588] Step 1: Under nitrogen protection, 2-benzyloxy-5-bromopyridine 79a (2.0 g, 7.57 mmol), methyl 3-pyrazolecarboxylate (1.05 g, 8.33 mmol), cuprous iodide (288.4 mg, 1.51 mmol), L-proline (174.4 mg, 1.51 mmol), and potassium carbonate (3.14 g, 22.72 mmol) were dissolved in dimethyl sulfoxide (5 mL). The reaction mixture was heated to 120 °C and stirred for 5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried, and the residue was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (elution system B) to give methyl 1-(6-(benzyloxy)pyridin-3-yl)-1H-pyrazole-3-carboxylate 79b (230 mg), yield: 9.8%. MS m / z (ESI): 310.1 [M+H] + .

[0589] Step 2: Under a hydrogen atmosphere, 79b (230 mg, 0.743 mmol) and palladium on carbon (27 mg, 0.223 mmol) were dissolved in methanol (5 mL), and the reaction was stirred at room temperature for 16 hours. The reaction solution was filtered, dried, and concentrated to obtain methyl 1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylic acid ester 79c (60 mg), yield: 36.8%. MS m / z (ESI): 220.1 [M+H] + .

[0590] Step 3: Under nitrogen 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 solution was diluted with ethyl acetate, washed with saturated brine, dried, and the residue was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (elution system B) to give methyl 1-(2-oxo-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-5-yl)-1H-pyrazole-3-carboxylic acid ester 79d (60mg), yield: 84.3%. MS m / z (ESI): 580.2 [M+H] + .

[0591] Step 4: Under nitrogen protection, 79d (60mg, 0.103mmol) was dissolved in anhydrous tetrahydrofuran (3mL) at 0℃. A tetrahydrofuran solution of methyl magnesium bromide (1M, 0.5mL) was added dropwise to the reaction solution. 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 give 5-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 79 (10.0mg), yield: 16.7%. MS m / z (ESI): 580.2 [M+H] + .

[0592] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.15(d,1H),8.05-7.95(m,3H),7.85(s,1H),7.48(dd,1H),7.15(dd,1H),7.04(d,1H),6.97(d ,1H),6.58(dd,2H),6.42(d,1H),4.96(s,2H),4.37-4.19(m,2H),2.17(dd,1H),2.03-1.87(m,2H),1.62-1.45(m,2H),1.44(s,6H).

[0593] Example 81

[0594] 4-(2-hydroxypropane-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0595]

[0596] Following the synthetic method of Example 58, the target product 4-(2-hydroxypropane-2-yl)-6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 81 was synthesized. MS m / z (ESI): 514.2 [M+H] + .

[0597] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),7.91(d,1H),7.85(s,1H),7.50(d,1H), 7.42-7.35(m,1H),7.17-7.11(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).

[0598] Example 82

[0599] 6-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[0600]

[0601] Following the synthetic method of Reference Example 3, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 82 was synthesized. MS m / z (ESI): 508.2 [M+H] + .

[0602] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.32(d,1H),7.90–7.82(m,2H),7.57–7.42(m,3H),7.14(dd,1H),7.01(d,1H),6.61( d,1H),6.54(d,1H),4.85(s,2H),4.38–4.15(m,2H),2.42(s,3H),2.22–2.11(m,2H),2.01–1.91(m,2H),1.66–1.44(m,2H).

[0603] Example 83

[0604] 6-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[0605]

[0606] Following the synthetic method of Reference Example 3, 6-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 83 was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0607] Example 84

[0608] 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-

[0609] (Isodihydroindol-1-one)

[0610]

[0611] Following the synthetic method of Reference Example 3, 2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 84 was synthesized. MS m / z (ESI): 494.2 [M+H] + .

[0612] Example 85

[0613] 5-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[0614]

[0615] Following the synthetic method of Reference Example 3, 5-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 85 was synthesized. MS m / z (ESI): 508.2 [M+H] + .

[0616] Example 86

[0617] 5-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[0618]

[0619] Following the synthetic method of Reference Example 3, 5-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 86 was synthesized. MS m / z (ESI): 512.2 [M+H] + .

[0620] Example 88

[0621] 7-Fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0622]

[0623] Following the synthetic method of Reference Example 3, 7-fluoro-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 88 was synthesized. MS m / z (ESI): 513.2 [M+H] +.

[0624] Example 89

[0625] 6-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0626]

[0627] Following the synthetic method of Reference Example 3, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 89 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0628] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,2H),8.31(d,1H),7.83(dd,2H),7.55(s,1H),7.14(dd,1H),7.02(d,1H),6.66(d,1H) ,6.54(d,1H),4.94(s,2H),4.38–4.15(m,2H),2.61(s,3H),2.22–2.11(m,2H),2.01–1.85(m,2H),1.63–1.47(m,2H).

[0629] Example 90

[0630] 6-Methyl-1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-carboxynitrile

[0631]

[0632] Following the synthetic method of Reference Example 3, 6-methyl-1-carbonyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-carboxynitrile 90 was synthesized. MS m / z (ESI): 534.2 [M+H]+ .

[0633] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.40(d,1H),7.97(s,1H),7.90–7.82(m,2H),7.18–7.11(m,1H),7.02(d,1H),6.77(d,1H),6.5 6(d,1H),5.19(s,2H),4.37–4.27(m,1H),4.26–4.14(m,1H),2.67(s,3H),2.23–2.09(m,2H),2.05–1.82(m,3H),1.67–1.42(m,2H).

[0634] Example 91

[0635] 2-Methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0636]

[0637] Following the synthetic method of Reference Example 3, 2-methyl-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 91 was synthesized. MS m / z (ESI): 509.2 [M+H] + .

[0638] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.34(d,1H),7.98(d,1H),7.87(dd,1H),7.85(s,1H),7.48(d,1H),7.15(d,1H),7.03(d,1H),6.68(d, 1H),6.56(d,1H),4.87(s,2H),4.33-4.28(m,1H),4.23-4.18(m,1H), 2.60(s,3H),2.19-2.12(m,2H),2.01-1.89(m,2H),1.61-1.48(m,2H).

[0639] Example 112

[0640] 6-(5-fluoro-6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0641]

[0642] Step 1: Reference Example 3e (150 mg, 0.53 mmol), 2,3-difluoro-5-nitro-pyridine (93 mg, 0.58 mmol), and cesium carbonate (428 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the mixture was 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 give (1S,3S)-N1-(3-fluoro-5-nitro-2-pyridyl)-N3-[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine 112a (180 mg), yield: 80.5%. MS m / z (ESI): 426.1 [M+H] + .

[0643] Step 2: Under a hydrogen atmosphere, 112a (158 mg, 0.37 mmol) and palladium / carbon (40 mg, 0.037 mmol, purity: 10%) were dissolved in methanol (10 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give 3-fluoro-N2-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridin-2,5-diamine 112b (131 mg), yield: 88.5%. MS m / z (ESI): 396.1 [M+H] + .

[0644] Step 3: 112b (131 mg, 0.33 mmol), methyl 3-(bromomethyl)pyridine-2-carboxylic acid (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 5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 112 (100.4 mg), yield: 70.7%. MS m / z (ESI): 513.2 [M+H] + .

[0645] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.76(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.85(s,1H),7.63(dd,1H),7.14 (dd,1H),7.01(d,1H),6.66(d,1H),4.96(s,2H),4.59–4.15(m,2H),2.24–2.10(m,2H),2.04–1.93(m,2H),1.68–1.51(m,2H).

[0646] Example 114

[0647] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-

[0648] )-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-5-one-7,7-d2

[0649]

[0650] Example 12 (30 mg, 0.061 mmol) was dissolved in tetrahydrofuran (2 mL) and heavy water (1 mL), and a 40% sodium deuterium oxide heavy aqueous solution (62 mg, 0.607 mmol) was added. The mixture was heated to 35 °C and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, filtered, concentrated, and the residue was purified by C18 chromatography (elution system C) to give 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-5-one-7,7-d2 114 (8.7 mg), yield: 28.9%.

[0651] MS m / z(ESI): 497.1 [M+H] + .

[0652] 1H NMR(400MHz,DMSO-d6)δ8.83-8.79(m,2H),8.37(d,1H),8.14(d,1H),7.90-7.84(m,2H),7.56(dd,1H),7.15(d,1H),7.03(d,1 H),6.68(d,1H),6.55(d,1H),4.33-4.28(m,1H),4.23-4.18(m,1H),2.20-2.13(m,2H),2.00-1.89(m,2H),1.60-1.50(m,2H).

[0653] Example 164

[0654] 6-(5-Fluoro-6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0655]

[0656] Step 1: Under nitrogen protection, 150 mg (0.6 mmol) of Reference Example 2c, 123 mg (0.7 mmol) of 2,3-difluoro-5-nitropyridine, and 233 mg (1.8 mmol) of N,N-dimethylformamide (5 mL) were dissolved in the solution. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to obtain (1S,3S)-N 1 -(3-Fluoro-5-nitropyridin-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 164a (200 mg), yield: 87%. MS m / z (ESI): 376.2 [M+H] + .

[0657] Step 2: Under a hydrogen atmosphere, 164a (200 mg, 0.5 mmol) and palladium on carbon (70 mg, 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]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine 164b (170 mg), yield: 97%. MS m / z (ESI): 346.2 [M+H] + .

[0658] Step 3: Under nitrogen 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 with stirring. The reaction was carried out at 25 °C with stirring for 16 hours, and then the temperature was raised to 85 °C with stirring 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 164 (20 mg) of 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, yield: 17%. MS m / z (ESI): 463.2 [M+H] + .

[0659] 1 H NMR(400MHz,DMSO-d6)δ8.76(dd,1H),8.65(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.63(dd,1H),7.27(dd,1H),6.86 (td,1H),6.74(d,1H),6.67(d,1H),4.96(s,2H),4.49(q,1H),4.16(q,1H),2.20–2.10(m,2H),1.98(dt,2H),1.63–1.52(m,2H).

[0660] Example 186

[0661] 5'-Fluoro-6'-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0662]

[0663] 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). The reaction mixture was heated to 100 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 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-fluoropyridin-2-yl)-N3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 186a (75 mg), yield: 71.86%. MS m / z (ESI): 409.1 [M+H] + .

[0664] Step 2: Under nitrogen protection, 186a (75 mg, 0.18 mmol), 2-pyridone (52 mg, 0.55 mmol), cuprous iodide (35 mg, 0.18 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.18 mmol) and cesium carbonate (119 mg, 0.37 mmol) were dissolved in 1,4-dioxane (1.5 mL), and the reaction was heated to 120 °C and stirred for 16 hours. A saturated ammonium chloride solution was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC (formic acid system) to prepare 186 (27.9 mg) of 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 35.95%. MS m / z (ESI): 424.2 [M+H] + .

[0665] 1 H NMR(400MHz,DMSO-d6)δ8.71-8.61(m,1H),7.84(d,1H),7.68-7.62(m,1H),7 .58-7.53(m,1H),7.52-7.46(m,1H),7.30-7.24(m,1H),6.94(d,1H),6.90-6 .82(m,1H),6.75(d,1H),6.46(d,1H),6.32-6.25(m,1H),4.62-4.42(m,1H), 4.24-4.09(m,1H),2.22-2.07(m,2H),2.05-1.88(m,2H),1.69-1.48(m,2H).

[0666] Example 418

[0667] 6'-(((1S,3S)-3-((6-(3-hydroxyazacyclobutane-1-yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0668]

[0669] Example 418 can also be prepared by the following method:

[0670]

[0671] 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 with stirring, followed by isopropanol (0.5 mL) and stirring for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and dissolved in dichloromethane (20 mL), followed by the addition of 2,3-dichloro-5,6-dicyanobenzoquinone (637.9 mg, 2.81 mmol). The reaction was stirred at room temperature for 1 hour. Dichloromethane (30 mL) was added to the reaction solution. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride solution (10 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine 418b (320 mg), yield: 73.5%. MS m / z (ESI): 232.0 [M+H] + .

[0672] 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 mixture was heated to 100 °C and stirred for 3 hours. The reaction solution was filtered, and the residue was separated by silica gel column chromatography (eluting 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), yield: 88.0%. MS m / z (ESI): 466.1 [M+H] + .

[0673] Step 3: Under nitrogen protection, 418C (100 mg, 0.214 mmol), 3-hydroxyazacyclobutane hydrochloride (117.5 mg, 1.07 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34.1 mg, 0.043 mmol), and cesium carbonate (698.7 mg, 2.14 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 100 °C with stirring for 16 hours. The reaction solution was filtered and purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product 6'-(((1S,3S)-3-((6-(3-hydroxyazacyclobutane-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 418 (15 mg), yield: 15.3%. MS m / z (ESI): 459.2 [M+H] + .

[0674] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.18(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.55(d,1H),4.51(m,1H),4.31(m,1H),4.15(m,1H),3. 98(t,2H),3.42(t,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.46(m,2H).

[0675] Example 422

[0676] 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0677]

[0678] Following the synthetic method of Example 418, 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 422 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0679] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.19(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.45(d,1H),4.30(q,1H),4.15(q,1H),3.66(d,2H),3. 52(d,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.45(m,2H),1.24(s,3H).

[0680] The synthesis method of the embodiments can be referred to the above embodiments.

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694] The NMR characterization data of the relevant embodiments are shown in the table below:

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702] Biological test evaluation

[0703] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0704] Experimental instruments and reagents:

[0705] 1. Instruments:

[0706] 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); Microplate shaker (Thermo: 88882006); Refrigerator (BCD-268TN, Haier); Biosafety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.); 5mL pipette (Research Plus, Eppendorf); 1mL pipette (Research Plus, Eppendorf). Plus, Eppendorf); Thermostatic water bath (HWS-12, Shanghai Yiheng Science); Electronic balance (BSA2202S-CW, CPA2202S, Sartorius); Ultrasonic cleaner (115F0032, Shanghai Kedao); Magnetic stirrer (08-2G, Chijiu); Fully automated blood biochemistry analyzer (Hitachi 7180).

[0707] 2. Reagents:

[0708] PCSK9-His (Sino Biology, 29698-H08H); Anti-His Tb (Revvity, 61HISTLF); Probe compound (Alexa Fluor 647 labeled, synthesized by Hansoh); DMSO (Sigma, D2650); HEPES buffer pH 7.5 (Beyotime, CO217); Sodium chloride solution (Beyotime, ST347); Calcium chloride solution (Beyotime, ST365); TWEEN20 (Sigma, P9416); 10% BSA (Thermo, 37525); 384-well plate (Revvity, 6007299); Compound dilution plate ( Biofil (VWP033096); 50 mL pipette tray (Corning, 4870); 50 mL centrifuge tubes (Corning, 430829); 2.5 μL pipette (Eppendorf, I36630F); 10 μL pipette (Eppendorf, J13131F); 100 μL pipette (Eppendorf, R22267J); 1000 μL pipette (Eppendorf, I44804F); 10 μL 12-channel electric pipette (METTLER TOLEDO, 17013797); 300uL 12-channel electric pipette (Eppendorf, O51743J); CircuLex Human PCSK9 ELISA kit (MBL: CY-8079); DMEM (Gibco: 31966-021); FBS (Sigma: S5394); compound plate (Thermo: 1353506); complete culture medium: DMEM + 10% FBS + 1X P / S; experimental culture medium: DMEM + 10% FBS; cell line: HepG2 (ATCC: HB-8065); Human LDL R Quantikine ELISA Kit (R&D: DLDLR0); PBS; Cell lysis buffer (Thermo: 78503); Protease inhibitor (Pierce: 78430); Alamethicin (Abcam); 7-Hydroxycoumarin (Sigma); Liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.); Phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7).4) NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bid Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck); high-fat diet (Western Diet, D12079B); physiological saline (MA0083-D, Meilunbio); Solutol HS15 (102483882, Sigma).

[0709] I. Combining experiments

[0710] Test Example 1: Determination of the binding ability of the compounds of the present invention to PCSK9 protein.

[0711] 1. Experimental objective: To detect the effect of compounds on the binding of PCSK9 protein using the HTRF method.

[0712] 2. Experimental Methods:

[0713] 1) Prepare a 1x experimental buffer solution with the following components: 20mM HEPES, 150mM NaCl, 1mM CaCl2, 0.01% Tween 20, and 0.01% BSA;

[0714] 2) Prepare a 2.5x final concentration PCSK9-His working solution (30nM) using 1x experimental buffer. Add 8uL of protein solution to each well of the 384-well plate except for the low control wells, and add 8uL of 1x experimental buffer to the low control wells.

[0715] 3) Preparation of compound working solution: First, the compound in the storage solution is uniformly serially diluted with DMSO (300 uM top, 3-fold, 10 doses). Then, 3.33 uL of each serially diluted compound is pipetted into 96.7 uL of 1x experimental buffer and mixed thoroughly to obtain the prepared compound working solution (10x).

[0716] 4) Pipette 2 μL of the compound into the corresponding well and incubate at 25°C for 10 minutes;

[0717] 5) Prepare a working solution of the probe compound at a final concentration of 4x using 1x experimental buffer (90 nM), mix thoroughly, add 5 μL to each well, and incubate at 25°C for 10 minutes;

[0718] 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;

[0719] 7) Envision reading HTRF665 / 615 program.

[0720] 3. Experimental data processing methods: XLfit four-parameter log(inhibitor) vs. response--Variableslope (four parameters) was used to fit the compound concentration, corresponding inhibition rate, and nonlinearity, and IC was calculated. 50 .

[0721] 4. Experimental Results:

[0722]

[0723]

[0724] 5. Experimental conclusions: As can be seen from the data in the table, the compounds in the embodiments of this invention have a significant binding effect on the PCSK-9 protein.

[0725] II. Cell Function Experiments

[0726] Test Example 1: Determination of the effect of the compound of the present invention on the concentration of PCSK9 secreted by HepG2 cells.

[0727] 1. Experimental objective: To detect the inhibitory effect of the compound on PCSK9.

[0728] 2. Experimental Methods:

[0729] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0730] 2) Digest and resuspend the cells in experimental culture medium, and seed 25,000 cells / well / 200μL into a 96-well cell culture plate and incubate at 37°C and 5% CO2 for 20-24 hours.

[0731] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[0732] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[0733] 5) Add the diluted compound to the cell culture plate at 250 μL per well and incubate at 37°C with 5% CO2 for 48 hours.

[0734] 6) Collect 200 μL of cell culture medium per well and freeze at -80℃ for later use.

[0735] 7) Take the cell culture medium sample out of -80℃ to dissolve, vortex, centrifuge, and set aside.

[0736] 8) Prepare standard curves: Add the corresponding volume of dilution buffer to each standard tube in sequence. Take the corresponding volume of standard from the original tube or the previous concentration tube in the order of concentration 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, 0 ng / mL and dilute it in sequence.

[0737] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[0738] 10) According to the plate map settings for standard curve wells and sample wells, add 100 μL of the corresponding standard and culture medium sample to each well, with 2 replicates. Seal with adhesive tape, place on a shaker at room temperature, gently shake to mix, and incubate for 1 hour.

[0739] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0740] 12) Add 100 μL of HRP-conjugated detection antibody to each well, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 1 hour.

[0741] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0742] 14) Add 100 μL of Substrate reagent to each well, protect from light, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 10-20 minutes.

[0743] 15) Add 100 μL of stop solution (1N H2SO4) to each well and mix well.

[0744] 16) Measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm using an ELISA reader. Perform the detection within 30 minutes after the reaction is terminated.

[0745] 3. Experimental Data Processing Method: The OD values ​​read by the microplate reader were subtracted from the OD values ​​of the standard group (0 concentration) from those of the standard, control group, and sample to obtain the actual values ​​for each well. A standard curve was then plotted using GraphPad to calculate the sample concentration. If the sample was over-diluted, the final calculation needed to multiply by the corresponding dilution factor to obtain the actual sample concentration. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to different concentrations, the IC50 was plotted using GraphPad.

[0746] 4. Experimental Results:

[0747]

[0748]

[0749] 5. Experimental Conclusion: As can be seen from the data in the table, the compounds in the embodiments of this invention showed a strong inhibitory effect on the concentration of PCSK9 secreted by HepG2 cells in the experiment.

[0750] Test Example 2: Determination of the effect of the compound of the present invention on LDLR levels in HepG2 cells

[0751] 1. Experimental objective: To detect the effect of the compound on LDLR protein levels.

[0752] 2. Experimental Methods:

[0753] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0754] 2) Digest and resuspend the cells in experimental culture medium, and seed 25,000 cells / well / 200μL into a 96-well cell culture plate and incubate at 37°C and 5% CO2 for 20-24 hours.

[0755] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[0756] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[0757] 5) Add the diluted compound to the cell culture plate at 250 μL per well and incubate at 37°C with 5% CO2 for 48 hours.

[0758] 6) Remove the cell culture medium, wash the cells with PBS, and add 50 pL of cell lysis buffer and protein inhibitor.

[0759] 7) Centrifuge to remove lysates and store the sample for later use.

[0760] 8) Prepare the standard curve: Add the corresponding volume of dilution buffer to each standard tube in sequence. Take the corresponding volume of standard from the original tube or the previous concentration tube in sequence and dilute it in sequence.

[0761] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[0762] 10) According to the plate map settings, add 80 μL of the corresponding standard and sample to each well, with two replicates. Wells without standards are used as background values. Seal with adhesive tape, place on a shaker at room temperature, gently shake to mix, and incubate for 2 hours.

[0763] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0764] 12) Add 200 μL of Human LDLR conjugate to each well, seal with an adhesive label, place on a shaker to mix thoroughly, and incubate for 2 hours.

[0765] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0766] 14) Add 200 μL of Substrate solution to each well, protect from light, seal with adhesive tape, place on a shaker to mix thoroughly, and incubate for 20 minutes.

[0767] 15) Add 50 μL of stop solution to each well, mix well, and incubate for 20 min.

[0768] 16) Use an ELISA reader to measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm.

[0769] 3. Experimental Data Processing Method: The OD values ​​read by the microplate reader were subtracted from the OD values ​​of the standard group (0 concentration) from those of the standard, control group, and sample to obtain the actual values ​​for each well. A standard curve was then plotted using GraphPad to calculate the sample concentration. If the sample was over-diluted, the final calculation needed to multiply by the corresponding dilution factor to obtain the actual sample concentration. The percentage increase in concentration (%) = (actual control concentration - actual sample concentration) / actual control concentration * 100.

[0770] 4. Experimental Results:

[0771]

[0772] 5. Experimental Conclusion: As can be seen from the data in the table, the compound in the embodiment of the present invention showed a significant effect on increasing the LDLR concentration in HepG2 cells.

[0773] III. Pharmacokinetic Experiments

[0774] Test Example 1: Pharmacokinetic Determination in Mice

[0775] 1. Experimental purpose: Using C57BL / 6J mice as test animals, study the pharmacokinetic behavior of the compound of the present invention after oral and intravenous administration in mice (plasma).

[0776] 2. Test protocol

[0777] 2.1 Test drug: The compound of the present invention, self-made;

[0778] 2.2 Test animals: C57 mice, male, purchased from Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK(Shanghai)2013-0006 N0.311620400001794).

[0779] 2.3 Drug preparation: Oral administration drug preparation: 10% Solutol HS15

[0780] Weigh 10 g of Solutol HS15 solid, dissolve it in 90 mL of purified water, mix evenly, stir and sonicate to form a clear solution. Weigh the compound of the present invention and dissolve it in this solution, shake well, sonicate for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL. Intravenous administration drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh the compound of the present invention, first add 5% DMSO according to the total administration volume ratio, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 um filter membrane to obtain a colorless transparent clear solution with a concentration of 0.2 mg / mL.

[0781] 2.4 Administration: 3 male C57 mice; after fasting overnight, administer PO respectively, with a dose of 5 mg / kg and an administration volume of 10 mL / kg. 3 male C57 mice; after fasting overnight, administer IV respectively, with a dose of 1 mg / kg and an administration volume of 5 mL / kg.

[0782] 2.5 Sample collection: Before and 0.083 (iv), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration to the mice, collect 0.04 mL of blood from the orbital cavity, place it in an EDTA-K2 test tube, centrifuge at 6000 rpm for 6 min at 4°C to separate plasma, and store it at -80°C; allow the mice to eat 4 hours after administration.

[0783] 2.6 Measurement results: The final measurement results are obtained by using the LCMS / MS method.

[0784] 3. Experimental results: The main pharmacokinetic parameters are calculated using WinNonlin 6.1.

[0785]

[0786]

[0787] 4. Experimental conclusions:

[0788] Pharmacokinetic studies in C57BL / 6J mice showed that the compound of this invention exhibited a good pharmacokinetic advantage. Example 2: Pharmacokinetic studies in cynomolgus monkeys.

[0789] 1. Research objective: To investigate the pharmacokinetic behavior of the compound of the present invention in cynomolgus monkeys (plasma) after oral administration at a dose of 5 mg / kg.

[0790] 2. Experimental Design:

[0791] 2.1 Experimental reagents: The compounds in the embodiments of this invention were prepared in-house.

[0792] 2.2 Experimental animals: 3 male cynomolgus monkeys per group, from Guangxi Xiongsen, Animal Production License No.: SCXK(Gui)2021-0004).

[0793] 2.3 Formulation: Oral administration drug preparation: 10% Solutol HS15 in water

[0794] Weigh 10g of solid Solutol HS15 and add it to 90ml of ddH2O in a 100ml volumetric flask. Vortex, mix, and sonicate to obtain a clear solution. Weigh the compound and add it to a 100mL glass bottle. Add the solution, vortex, and sonicate for 10 minutes to obtain a white suspension with a concentration of 1mg / mL.

[0795] 2.4 Administration: Three male cynomolgus monkeys were fasted overnight and then administered orally; the dose was 5 mg / kg, and the administration volume was 5 mL / kg.

[0796] 2.5 Sample collection: Blood collection: 0.3 mL of blood was collected from the forelimb veins of cynomolgus monkeys before and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after drug administration. The blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 6000 rpm for 6 min at 4℃ to separate plasma. The plasma was stored at -80℃. The monkeys were fed 4 hours after drug administration.

[0797] 2.6 Sample preparation:

[0798] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0799] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000 Qtrap.

[0800] ●Liquid phase analysis: Liquid phase conditions: Shimadzu LC-20AD pump

[0801] ● Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile Flow rate: 0.4mL / min

[0802] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0803]

[0804] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0805] 4. Experimental Conclusions: Pharmacokinetic analysis results in cynomolgus monkeys showed that the compounds of this invention exhibited good pharmacokinetic advantages, with the compound AUC being [missing information]. 0-∞ (ng / mL×h) ranges from 20,000 to 50,000, with the AUC of the dominant compound being... 0-∞ (ng / mL×h) is 30,000 to 50,000.

[0806] Test Example 3: In vitro metabolic stability study of the compounds of the present invention in mouse, rat and human liver microsomes

[0807] 1. Experimental objective: The objective of this experiment is to evaluate the metabolic stability of the compound in phase I and part of phase II in mouse, rat and human liver microsomes.

[0808] 2. Experimental Design

[0809] 2.1 Drug Preparation: The compounds of this invention were prepared into 10 mM stock solutions using DMSO (or other suitable solutions) and stored at -20°C for later use. The compounds of this invention were prepared in-house.

[0810] 2.2 Experimental Procedure

[0811] 1) Prepare buffer solution: Take 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dissolve them in ultrapure water and bring the volume to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0812] 2) Preparation of working solution: Add 2 μL of the compound stock solution to 998 μL of phosphate buffer to achieve a final concentration of 20 μM. The ratio and final concentration can be adjusted according to the properties of the compound.

[0813] 3) Prepare liver microsome working solution: 156.3 μL of 20 mg / mL microsomes, diluted to 5 mL with 100 mM phosphate buffer, mixed well, with a final concentration of 0.625 mg / mL.

[0814] 4) Prepare NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

[0815] 5) Prepare the pore-drilling agent (Alamethicin): Weigh 1 mg of Alamethicin and add it to 200 μL of methanol to prepare a solution of 5 mg / mL. Then take 10 μL of this solution and add it to 990 μL of phosphate buffer (pH 7.4) to obtain a final concentration of 50 μg / mL.

[0816] 6) Prepare the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution and store it in a refrigerator at 2-8℃.

[0817] 7) Incubation Procedure: Add 400 μL of prepared liver microsomes, 25 μL of the compound working solution (20 μM), and 25 μL of Alamethicin (50 μg / mL) sequentially to a 96-well plate, and pre-incubate at 37°C for 10 min. Then add 50 μL of prepared NADPH / UDPGA to initiate the reaction and incubate at 37°C. The total reaction volume is 500 μL. The final concentrations of each component are as follows:

[0818]

[0819] At time points of 0, 5, 15, 30, 60 and 120 min, 50 μL of each sample was taken and 200 μL of cold stop solution containing internal standard was added to terminate the reaction. The sample was centrifuged at 3500 rpm for 10 min and the supernatant was taken for LC-MS / MS analysis.

[0820] 2.4 Chromatographic Analysis

[0821] 1) Chromatographic conditions:

[0822] Instrument: Shimadzu LC-20AD; Column: Phenomenex C18 (50*4.6mm, 5μm particle size); Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile; Wash gradient: 0.2–1.6 min 5% A to 95% A, 3.0–3.1 min 95% A to 5% A; Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 μL.

[0823] 2) Mass spectrometry conditions

[0824] Instrument: API4000 liquid chromatography-mass spectrometry system, AB Sciex; Ion source: electrospray ionization source (ESI); Dry gas: N2, temperature 500℃; Electrospray voltage: 5000V; Detection mode: positive ion detection; Scan mode: reaction monitoring (MRM); Scan time: 0.8401s.

[0825] 3. Data Processing: Calculate the raw data using the following formula:

[0826] Residual percentage % = (Peak area ratio of compound to internal standard at any time point) / (Peak area ratio of compound to internal standard at 0 minutes) × 100

[0827] T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0828] In vitro intrinsic clearance rate of liver microsomes (CL) was calculated using Ke. int ) and hepatic intrinsic clearance (CL) int,liver )

[0829] CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL)

[0830] CL int,liver =CL int × Liver microsomal protein content (mg / g) × Liver weight to body weight ratio

[0831] Based on the well-stirred model, the in vivo liver clearance rate (CL) was estimated. int,liver )

[0832] CL = (CL) int,liver ×fu×Qh) / (CL int,liver ×fu+Qh), where fu represents the free fraction in the blood, which is 1 by default. The parameters in the formula are shown in the table below.

[0833]

[0834] 4. Experimental Results:

[0835]

[0836] 5. Experimental conclusions: The results show that the compounds of the advantageous embodiments of the present invention exhibit stable metabolic effects in various liver microsomes, especially in human liver microsomes.

[0837] IV. Drug Efficacy Experiment

[0838] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0839] 1. Experimental objective: To evaluate the in vivo efficacy of the compound in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0840] 2 Experimental Operation and Data Processing

[0841] 2.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[0842] 2.2 Animal Model: After animals arrived at the barrier system, they were allowed to adapt for one week before being fed a high-fat diet. Animal weight and feed intake were recorded weekly.

[0843] 2.3 Grouping and Administration

[0844] a. Grouping is done using a random grouping method.

[0845] c. Based on the grouping results, begin administering the test drug (administration route: oral; administration volume: 10 mL / kg; administration frequency: once daily or single dose; administration period: 21 days; solvent: 10% Solutol HS15 / 90% Saline). Test drug: the compound of this invention, prepared in-house.

[0846] d. After starting the test drug, weigh and feed twice a week, and collect blood once a week.

[0847] e. Process data using software such as Excel. Body weight change rate (BWC) (%) = (Weight at the end of treatment - Weight at the beginning of treatment) / Weight at the beginning of treatment × 100%; Feed intake (g / mice / day) = (Previous feed addition + Previous feed residue - Current feed residue) / Number of animals / Number of feeding days; Calculation of blood biochemical inhibition rate: Using the blood biochemical results of the Vehicle group tested in the same batch as a baseline, normalize the data of each treatment group, and then calculate the percentage of TC and LDL-C according to the formulas: TC change percentage (%) = (TC value after administration - TC value before administration) / TC value before administration * 100%; LDL-C change percentage (%) = (LDL-C value after administration - LDL-C value before administration) / LDL-C value before administration * 100%. Detect PCSK9 in plasma using ELISA.

[0848] 3. Experimental Results:

[0849]

[0850] 4. Experimental conclusion: The compounds in the embodiments of this invention can effectively reduce LDL-C in the B6-hPCSK9 transgenic mouse model of hyperlipidemia.

Claims

1. A compound of general formula (I-1-a), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ring B is selected from , , , , or ; R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl or cyclopropyl; R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 alkyl; R c-1 Selected from halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or cyclopropyl; R c-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 alkyl; y is 0, 1, 2, or 3; e can be 0, 1, 2, or 3; and The compound is not , , or .

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound is further shown as in general formula (I-1-a'): 。 3. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, Ring B is selected from , , or .

4. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl.

5. The compound according to any one of claims 1-3, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R b Choose from -H or -F.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 3, characterized in that, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2 or ; And / or, R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3 or -O-CH(CH3)2; And / or, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3 or -O-CH(CH3)2.

7. The compound according to any one of claims 1-3, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that, R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, or -OH.

9. The compound according to any one of claims 1-3, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or cyclopropyl.

10. The compound according to any one of claims 1-3, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that, R a-1 ~R a-4 Each is independently selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3 or .

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

12. A compound of general formula (IV), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: X2 is amino, nitro, halogen, boric acid, or borate ester; Ring A is ; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl or cyclopropyl; The other groups are as described in claim 1.

13. The compound of general formula (IV) according to claim 12, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Selected from the following compounds: or .

14. A method for preparing a compound of the general formula as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It includes the following steps: in: X2 is amino, nitro, halogen, boric acid, or borate ester; X3 is hydroxyl, amino, methylthio, halogen, boric acid or borate ester; Ring A is ; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl or cyclopropyl; The reaction of compound of general formula (IV) with compound of general formula (IV-1) yields compound of general formula; The other groups are as described in claim 1.

15. A pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown in claims 1-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

16. An oral pharmaceutical formulation comprising 0.5% to 85% by weight of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof are further shown as in general formula (I-1-a): in: Ring B is selected from , , , , or ; R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 alkyl; R c-1 Selected from halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or cyclopropyl; R c-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl; R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl or cyclopropyl; y is 0, 1, 2, or 3; or e can be 0, 1, 2, or 3.

17. The oral pharmaceutical preparation according to claim 16, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof account for 1% to 60% by weight.

18. The oral pharmaceutical preparation according to claim 17, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 10% to 50% by weight.

19. The oral pharmaceutical preparation according to claim 18, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 15%-40% by weight.

20. The oral pharmaceutical preparation according to claim 19, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 20%-30% by weight.

21. The oral pharmaceutical preparation according to claim 20, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 20%-25% by weight.

22. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof are further shown as in general formula (I-1-a'): 。 23. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, Ring B is selected from , , or .

24. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl.

25. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R b Choose from -H or -F.

26. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2 or ; And / or, R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3 or -O-CH(CH3)2; And / or, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3 or -O-CH(CH3)2.

27. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl.

28. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, or -OH.

29. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or cyclopropyl.

30. The oral pharmaceutical preparation according to any one of claims 16-21, characterized in that, R a-1 ~R a-4 Each is independently selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3 or .

31. An oral pharmaceutical formulation comprising 0.5% to 85% by weight of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients, characterized in that, It contains the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: or .

32. The oral pharmaceutical preparation according to claim 31, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof account for 1% to 60% by weight.

33. The oral pharmaceutical preparation according to claim 32, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 10% to 50% by weight.

34. The oral pharmaceutical preparation according to claim 33, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 15%-40% by weight.

35. The oral pharmaceutical preparation according to claim 34, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 20%-30% by weight.

36. The oral pharmaceutical preparation according to claim 35, characterized in that, The compound, its stereoisomers, or pharmaceutically acceptable salts thereof constitute 20%-25% by weight.

37. An oral pharmaceutical preparation comprising a therapeutically effective dose of any of the compounds shown in claims 1-11, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 15.

38. The use of any compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the pharmaceutical composition of claim 15, or the oral pharmaceutical preparation of any one of claims 16-37 in the preparation of a medicament for the treatment of cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms.

39. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or the pharmaceutical composition according to claim 15, or the oral pharmaceutical formulation according to any one of claims 16-37, in the preparation of a medicament for the treatment of stroke, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

40. The use of the compound and its stereoisomer or pharmaceutically acceptable salt thereof as shown in any one of claims 1-11, or the pharmaceutical composition of claim 15, or the oral pharmaceutical formulation of any one of claims 16-37 in the preparation of a medicament for treating dyslipidemia and / or dyslipoproteinemia.

41. The use of the compound or stereoisomer of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, or the oral pharmaceutical formulation of any one of claims 16-37, in the preparation of a medicament for treating hyperlipidemia and / or hyperlipoproteinemia.

42. The use of the compound and its stereoisomer or pharmaceutically acceptable salt as shown in any one of claims 1-11, or the pharmaceutical composition of claim 15, or the oral pharmaceutical formulation of any one of claims 16-37 in the preparation of a medicament for treating hypercholesterolemia and / or hypertriglyceridemia.

43. The application according to any one of claims 38-42, characterized in that, The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or oral pharmaceutical preparation is administered once daily.

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